Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Nanocarriers surface engineered with cell membranes for cancer targeted chemotherapy

Nanocarriers surface engineered with cell membranes for cancer targeted chemotherapy Background delivered through nanoparticles has not yet achieved Cancer has been a worldwide concern for a long period its full therapeutic potential. of time and is the second largest cause of mortality [1]. The drug-delivery system’s (DDSs) technology contin - Conventional chemotherapy, as one of the most fre- ues to advance, making it possible to administer more quently used methods for cancer treatment, remains potent drugs [9]. Drug research efforts are significantly unsatisfactory owing to the significant side effects and aided by therapeutic compounds’ capacity to remain the poor targeting ability of anti-cancer drugs [2]. To intact in a hostile extracellular milieu [10]. In this con- overcome these issues, significant research and devel - nection, efforts to reduce immunogenicity and improve opment has been conducted on targeted drug delivery biopharmaceutical stability through modification of systems (TDDS), particularly nanocarrier-based TDDS biopharmaceuticals have increased [11]. Cells in the early [3]. The benefits of nanocarriers, which include the 1980s were used as drug delivery vehicles, which substan- ability to be modified, a large capacity for drug load - tially increased the drugs’ retention and targeting capa- ing, and tunable physiochemical characteristics, make bilities [12]. Despite the increasing use of live cell-based them ideal for encapsulating anti-cancer drugs and carriers, several shortcomings persist. One major con- altering their stability, solubility, and in  vivo behaviour cern is passenger drug activity, as drugs may be digested [4]. Nevertheless, surface modification of nanocarriers by the cell carrier’s lysosomes [13]. Moreover, drug may enhance their blood circulation and enable more release is difficult to control due to exocytosis or leak - precise targeting, thus increasing effectiveness while age during transport [14]. Faced with these challenges, trying to minimize side effects [5 ]. However, there are scientists recently discovered a natural way to design also many disadvantages that make it difficult for nano - biomimetic cell membrane nanocarriers. At first, the bio - carriers to live up to clinical standards. The immune mimetic cell membrane nanocarriers were made from a system recognizes and eliminates the majority of nano- poly (lactic-co-glycolic acid) (PLGA) core and a red blood carriers as foreign substances. Since the polyethylene cell (RBC) membrane shell, using a co-extrusion process glycol (PEG), a hydrophilic polymer, was initially incor- [15]. Then, different cell membrane-coated nanocarriers porated into a protein medication [6], PEGylation has (CMCNs) were explored with different nanocarrier cores been the most frequently utilized modification tech - and membrane materials. The incorporation of nanocar - nique in drug delivery applications [7]. Additionally, riers into the cell membrane merges the advantages of the targeted capacity of nanocarriers was highly reli- material science and biomimicry. It is important to note ant on the surface modification, which was challenging that CMCNs can be portrayed as autogenous cells to pro- to manufacture and accomplish [8]. As a result, TDDS long blood circulation time and avoid immune system L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 3 of 21 elimination, both of which are required for the enhanced to the whole cell. Because a longer circulation time ben- permeability and retention (EPR) effect of cancer tar - efits with the potential of sustained drug delivery and geted chemotherapy [16] (Fig. 1). increases the probability of sustained distribution into Moreover, different cell membranes may confer dif - the circulation [20]. The biomimetic CMCNs provide ferent functions on CMCNs, resulting in varying in vivo bio-modulation and more control in this regard. The behaviour. Biomimetic technology, a relatively new pro- CMCNs prepared by coating RBC membrane on PLGA cedure, satisfies these requirements and is currently nanocarriers improved the nanocarriers’ retention in being used in designing drug nanocarriers [17, 18]. By the blood by 72 hours, compared to 15.8 hours for typi- drawing inspiration from nature that comprises biologi- cal synthetic stealth nanocarriers [15]. Moreover, PLGA cal elements and living matter, this technology aims to nanocarriers with a fluorocarbon core masked in an overcome the shortcomings of current drug delivery sys- RBC membrane were used for delivering oxygen to solid tems. An ideal biomimetic delivery system exploits path- tumours, demonstrating another application of CMCNs ogens’ immune evasion and intracellular uptake tactics. delivery to improve blood circulation time via the EPR However, delivery systems derived from pathogens con- approach [21]. tinue to raise safety concerns, including immunogenicity The reduced immunogenic characteristics of cancer and virulence [19]. cell membranes and their homing abilities improve tar- geted drug delivery at the cancer site. In this respect, Cao Advantages of CMCNs based drug delivery systems et  al. investigated the interaction between VCAM-1 of CMCNs have notably contributed to suppressing drug metastatic cancer cells with macrophage α4 proteins to resistance in the use of nanocarriers for cancer thera- transport cytotoxic anticancer drugs to the lungs [22]. pies. Biomimetic CMCNs possess special characteristics, Using the adhesion characteristics of galectin-3 and T such as prolonged drug delivery, immunological eva- antigen in cancer cell membranes, Fang et  al. demon- sion, homotypic targeting, longer blood circulation, and strated homotypic tumour targeting [23]. Furthermore, specific ligand/receptor recognition. To get beyond the when compared to other active targeting methods, incor- restrictions of cell toxicity, differentiation, and sensitivity porating iron oxide nanocarriers into fractured cancer in cell-based delivery systems, CMCNs utilize therapeu- cell membranes for tumor targeting demonstrated supe- tically relevant cell membrane proteins as an alternative rior homing to homologous tumors in vivo [24]. Recently Fig. 1 Nanocarriers with a cell membrane coating for cancer drug delivery. Different types of cell membranes are used to encapsulate various types of nanocarrier core for cancer treatment Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 4 of 21 designed leuko-like vectors (LLV) targeting metastatic therapy [33]. For example, the membrane of RBCs is niches utilizing neutrophil membrane-coated nanocarri- rich with glycophorins that play a key role in attracting ers have shown a two- to threefold increase in metastatic pathogens to their surface and killing them via oxytosis foci accumulation compared to PLGA-PEG nanocarri- [32]. The application of an RBC membrane to the nano - ers and bare nanocarriers, respectively [25]. This affin - carriers thereby increases pathogen clearance, long- ity for metastatic niches is enhanced by the presence of term circulation, and cell viability. Platelets interact with N cadherin, Mac-1, and other sticky proteins produced injured endothelial cells and engage with immune cells on neutrophil membranes on CMCNs, as opposed to to mobilize them toward the inflamed site [34]. As a the usual PEG coating employed to prolong circulation result, covering the nanocarriers with the platelet mem- half-life and prevent clearance [26]. Interestingly, PLGA branes allows for selective adherence to tumour tissues nanocarriers coated with T lymphocyte membranes were or wounded vessels, targeting circulatory tumour cells, also capable of retaining their lymphocyte coating and pathogen eradication, and the capability to elude detec- evading lysosome sequestration, while bare nanocarri- tion by macrophages. Similarly, macrophage membranes ers were caught in endolysosomal compartments prone like other leukocytes carry adhesion molecules like to breakdown in in  vivo [27]. Moreover, this study also VLA-4, LFA-1, PSGL-1, L-selectin, and P-selectin that discovered that T lymphocyte-coated nanocarriers had a help with cell adherence [35]. u Th s, coating the nanocar - twofold increase in particle density throughout tumours rier with macrophage membrane has the ability to bind in mice when compared to naked nanocarriers. Numer- pathogens while avoiding macrophage recognition and ous additional research groups are attempting to harness offering active targeting at the cancer site. Moreover, the cell membrane’s inherent properties to create biomi- tumor-specific adhesion molecules and antigens such as metic drug carriers for cancer treatments. mucoprotein-1, epithelial-adhesion molecules, lympho- cyte-homing receptors (like CD44), galectin-3, integrins, Considerations of CMCNs and cadherins are overexpressed on the surface of cancer Choice of cell membrane cell membranes [36]. These antigens and adhesion mol - A thorough understanding of the homeostasis, func- ecules play a critical role in the contacts among cells and tion, and structure of cells in their complex physiologi- between cells and the surrounding tissue matrix. Gener- cal context provides key hints for better biointerfacing ally, cancer cell membranes can cling to their homolo- of synthetic DDSs [28]. A delivery system with the abil- gous cells [37]. So, wrapping a nanocarrier with a cancer ity to protect cargo and carry cell features like autono- cell membrane prevents macrophage detection, allowing mous activity, compartmentalization, flexibility, and for homotypic tumour targeting, and contributes to the form can be more convenient and beneficial than other design of personalized cancer therapy. delivery systems. The cell membrane repeats the surface functionality of cells and extracellular vesicles as it is the Cell source fundamental structural component of them. It is primar- In order to use maximum cell membrane properties, ily made up of carbohydrates, proteins, and lipids, and it is essential to consider the state, form, and source of it interacts with the environment to survive and grow the cell. In this connection, Evangelopoulos et  al. dem- [29]. Carbohydrates play a part in cellular recognition, onstrated that the cell source determines the immuno- whereas proteins are responsible for adhesion and sign- genicity of biomimetic nanocarriers [38]. They studied aling, and lipid bilayer formation combines structural multilayer cell membrane generated vesicles from various fluidity and stiffness [30–32]. Cell membranes can be dif - sources for phagocytosis, opsonization, and targeting of ferentiated based on the properties and composition of inflamed regions. Literature showed that the use of a syn - these three components in them. The potential to profit geneic cell membrane coating increased the avoidance from native cell membrane functions has sparked tre- of absorption by the liver and immunological repertoire mendous scientific interest in coating nanocarriers. If cells [38]. To isolate the cell membrane for the coating done appropriately, the cell membrane retains its capabil- of nanocarriers, it is preferred to choose homotypic cells ity, and its coating enhances biointerfacing. in a healthy state and nourishing phase. The real thera - The selection of the appropriate cell type or cell mem - peutic effectiveness of CMCNs requires homogeneity of brane is crucial for ensuring site-specific distribution the cell population. To fulfil this requirement, quanti - and targeting as well as for minimizing adverse interac- fication or expression levels of specific surface markers tions with complementing systems in vivo. Every cell type (e.g., receptors or ligands) plays a dominant role. For this has unique biological features, making them suitable for purpose, flow cytometry, Blot Western, and SDS-PAGE certain therapeutic applications such as infectious dis- techniques can be used to evaluate the cellular state and eases, inflammatory diseases, cancer, and personalized homogeneity of cell membranes [39]. Identification of L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 5 of 21 cell biomarkers and other ligands for signal transduction, of mesenchymal stem cells, which vary across individu- targeting, or any other approach would enhance transla- als, cell groups, and even batches. The expansion of mes - tional effects. enchymal stem cells in in  vitro not only alters mRNA expression patterns but also affects the surface proteins Membrane stability involved in migration and adhesion (e.g., C-met/HGF, CMCNs are preferred for use over targeting nanocar- CXCR7, CXCR4, etc.) [44]. In the case of nanocarriers riers prepared via a bottom-up approach because they coated with immune cell membrane, it is essential to con- possess numerous characteristics, including signal trans- sider the state and cellular source of immune cells, since duction, immune evasion, targeting, and therapeutic they undergo different modifications throughout the advantages. To maximize the therapeutic potential of pro- and post-inflammatory phases (e.g., pro- and post- CMCNs, the structural and functional characteristics of inflammatory macrophages M1 and M2). the cell membrane should be preserved prior to coating While obtaining the desired membranes is still an drug carriers. The cell membrane’s stability is critical in attractive approach, it is becoming increasingly favora- determining the overall durability of CMCNs. The micro - ble to modify the cell surface using proteins, peptides, or environment of tissue and circulation naturally creates small molecules before harvesting the membranes [45]. torque and shear forces on cells and nanocarriers. Cells In this scenario, cell membrane receptors are becoming survive with these forces and respond to them by actively less sensitive, and this is unknown at this time. In the case modulating their cytoskeleton-membrane interactions, of highly biotinylated membranes of erythrocytes, they lipid profile, ligand density, and ligand concentration. For are more likely to be taken up by macrophages because of example, the interaction of intracellular proteins with the the presence of C3b proteins on them. It is suggested that cell membrane strengthens the reliability of natural cells. biotinylation may also disable complement regulators or During the isolation of the membrane, some key stability self-markers on the cell surface [46]. As CMCNs appear regulators of the cell membrane may be lost or changed. to have no significant effect on cellular behaviours, they As a result, determining the overall membrane stability do not entirely reflect what the cells naturally do. Stephan of CMCNs becomes critical before moving further with et al. performed a detailed investigation of nanocarriers- biomimetic-based treatment [40]. Numerous techniques tethered T cells to monitor synapse formation, transmi- for determining the stability of membrane structures are gration, antigen, and cell division. They found that the described in the literature. For visualizing the structural ability of the cell to perform physiological functions was integrity and morphology of cell membranes, advanced not affected by the conjugation of nanocarriers to the cell fluorescence, lipophilic dye enhanced, Cryo-TEM, and membrane [40]. The degree of immune response vari - spectrophotometric techniques, for example, are all ability is proportional to the variety of different sources extremely useful [41]. When it comes to the mechanical employed in cell membrane engineering and to the tech- or elastic integrity of membranes, ektacytometry may nology used to design the membranes. To successfully be the best tool for determining membrane elongation apply biomimetic-based drug delivery applications to the in dynamic shear stress [42]. Additionally, the source of clinic, it is essential to have extensive CMCNPs charac- lipid composition in the cell also influences the overall terization and qualification. stability of CMCNs. In one study comparing the lipid- omic profiles of cells, a higher proportion of unsaturated Cell membrane extraction phospholipids was observed in primary cell cultures than In order to successfully isolate the cell membrane, cell other cultured. X-ray scattering, FTIR, and colorimetric membrane extraction protocols must ensure that there lipid assays are all useful tools for assessing the qualita- is minimal or no cytosol, mitochondrial, or nuclear tive composition of phospholipids [43]. contamination. Making use of a pure cell membrane improves surface coating efficiency and uniformity, Membrane‑related proteins allowing for maximum functional and structural replica- The CMCNs interact with the local environment of tis - tion on the nanocarrier surface. To preserve membrane sues and cells through proteins present on the cell mem- proteins from degeneration, the extraction medium is branes. So, the appropriate membrane proteins must supplemented with phosphatase/protease inhibitor cock- be kept up in the cell culture. Several transfection and tails that are stored at ice-cold temperatures. Prior to chemical signaling methods may be used to regulate extraction, cells are thoroughly cleaned with saline buffer protein expression and cellular states in culture. In fact, to remove any remaining remnants of the cell culture long-term cell growth of some cell types may alter their medium. desirable characteristics for CMCNs applications. For Some cells lack nuclei (e.g., RBCs and platelets), mak- example, the culture condition affects the phenotypes ing membrane extraction easy. During membrane Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 6 of 21 extraction, cells are separated first from their tissues classified as organic and inorganic, where liposomes, using the most suitable techniques. For RBCs, a hypo- gelatin, and PLGA are organic templates, while inorganic tonic treatment certainly disintegrates the cells and frees templates include iron oxide (F e O ), gold, mesoporous 3 4 the cell membrane to collect through centrifugation in silica, upconversion nanoparticles (UCNPs), PLNPs, and the form of a pink RBC pallet [47]. Again and again, cen- MOFs. Organic templates are simple to use and provide trifugation purifies the pallet from haemoglobin impu - benefits, including biocompatibility, biodegradability, and rities. For platelets, it is recommended to do multiple nontoxicity [53]. Inorganic templates, on the other hand, freeze–thaw sequences to rapture their membrane by have electrical, optical, and magnetic properties that breaking ice crystals to release the cytosol [48]. The free influence their selection in a CMCN [54]. cell membrane is then collected through centrifugation. For clinical translation, template biodegradability and Sometimes, the collected platelet membranes are treated biocompatibility are critical which are influenced by the with a discontinuous sucrose gradient to purify the plate- degradation and byproducts formation and their sub- let membrane from any high-density granules, proteins, sequent interactions with human body. 231,231 Renal and intact platelets. clearance helps avoid the templates adverse effects [55]. Extraction of the membrane from nucleus-containing FDA-approved templates are regarded the safest in terms cells is slightly more difficult than from nucleus-free cells. of toxicities. Because most organic templates are safer Nucleus-containing cells include β-cells, fibroblasts, can - than inorganic ones, they have been practiced in clini- cer stem cells, and immune cells (e.g., T cells, NK cells, cal trials [56]. In 2011, a PLGA nanoparticle was used neutrophils, monocytes/macrophages). These cells can as a template to build these imitating systems [15]. As be isolated from established cell lines like MCF-7, 4T1, a synthetic polymer, PLGA can be fabricated into nano J447, NK-92, etc., or from blood or tissues (stem cells, and microparticles and have been commonly used for cancer cells, T cells, neutrophils, NK cells, etc.). By com- RBC, platelets, cancer cells, neutrophils, dendritic cells, bining hypotonic treatment with physical disruption pro- macrophages, cardiac stem cells, and various other tem- cedures, it produces an extract that contains high-density plates [47, 49, 57–60]. Gelatin, a natural polypeptide granules, intact cells, and free cell membranes. Finally, widely used in medicines, food, and cosmetics, has also the cell membrane is isolated from the mixture through been utilized for assembly of CMCNs. Patient-derived the use of discontinuous sucrose gradient ultrafiltration tumour cells, T-cell, stem cell, and RBC are employed to or differential centrifugation [49, 50]. coat gelatin templates for CMCNs [61–64]. Liposomes Membrane functional components such as cholesterol have also been used as core for cancer cells, RBCs, and (making structural components), carbohydrates (cellular macrophages membranes [22, 65, 66]. Perfluorocarbons recognition components), and transmembrane proteins (PFCs) are also among the regulated templates where (adhesion and signaling components) can be lost dur- PFCs (Fuosol-DA) was approved in 1989 but was with- ing membrane isolation. Cholesterol helps keep the cell drawn from market shortly due to storage issues [67]. membrane rigid. This loss may reduce the membrane’s However, PFCs are biocompatible, biodegradable, and mechanical stability. Moreover, proteins also act as mem- have high oxygen-carrying capacity with ~ 20 times brane skeleton stabilizers by selectively attaching to the greater than water thus can be used for oxygen delivery junction complex as well as other membrane proteins to smallest capillaries and hypoxic tumour locations [68]. such as tropomyosin [51]. Therefore, hypotonic buffers The toxicity of inorganic templates depends on the type containing divalent ions (such as MgCl ) or even add- of utilized metal and its breakdown in  vivo. Silica is the ing cholesterol can be effective in reducing protein loss safest (FDA-approved) inorganic template and is biode- while maintaining membrane stability [52]. Moreover, gradable and biocompatible [69]. It has been a research the right pH, soft rapturing procedures, proper ice-cold focus for templates due to certain properties including conditions, and mild lysis buffer must be adopted for high surface area, porosity, and drugs or photosensitiz- membrane extraction to avoid denaturation of trans- ers loading capability [70]. CMCNs have been reported membrane proteins/receptors. Once the cell membrane using spherical silica nanoparticles on RBC, cancer cells, has been isolated, it is freeze dried and kept at −  80  °C and macrophage membranes [71, 72]. Mesoporous silica to ensure that membrane proteins retain their long-term nanoparticles can be tuned and chemically modified into consistency and features. various shapes and sizes for desired applications, e.g., prolonged antibacterial property and regulating endoge- Choice of template nous reactive oxygen species for oxidative treatment [73]. A template is a structural component of the CMCNs When combined with CMC mimics, these tunable fea- which can be used for diagnosis and drug delivery tures could offer therapeutic benefits. The surface charge due to its various desirable features. Templates can be of silica templates can be changed with 3- aminopropyl L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 7 of 21 triethoxysilane for CTC detection [74, 75]. Iron ions are to lysate them. Second, the purification of the mixture harmless biodegradation products of Fe O nanoparti- to separate cellular components and cell membranes by 3 4 cles. MSCs and HeLa cells were employed as membranes centrifugation [83]. The centrifugation process will be in several CMC mimics employing Fe O templates [76– different depending on the cell type. For example, irregu - 3 4 78]. MOFs are 3D structures generated by the complexa- lar sucrose gradient centrifugation is needed to prepare tion of organic ligands and metal ions [79]. Their toxicity eukaryote cell membranes because this treatment sepa- is associated with the type of organic linkers and met- rates the membrane from nuclei and other cell compo- als employed. For example, zinc-based MOFs [zeolitic nents. Whereas nuclei-free membranes like RBCs do not 2+ imidazolate (ZIF-8)] degrade to release Zn ions, an require this treatment. Third, preparation of the inner endogenous element with a less detrimental effect on the core. Liposomes, gelatin, PLGA, poly (-caprolactone), human body [80]. Post-degradation of TPP-based Gd/Zn iron oxide nanoparticles, gold nanoparticles, mesoporous 3+ 2+ MOFs releases gadolinium (Gd ) and zinc (Zn ) ions, silica nano-capsules, silicon nanoparticles, and other syn- 3+ where Gd is harmful to the kidneys and can pass the thetic materials make up the inner cores. The inner core blood–brain barrier to accumulate in the brain [81]. Due selection for CMCNs is based on the types of cargo to be to their structural arrangement, MOFs have excellent transported (Fig. 2). porosity, surface area, and photosensitizer loading capa- To prepare CMCNs, the inner core nanoparticles and bility. Gold microparticles are another inorganic tem- the cell membranes are fused together. The fusion pro - plate, but they are not biodegradable and may be harmful cess must be carried out in such a way that it should not thus, nano or ultra-small templates of gold for fast renal result in protein denaturation or drug leakage. The two clearance is ideal [82]. Gold particles can be shaped into most frequently used procedures for the fusion of the nanoparticles, nanoshells, nanorods, and nanocages, inner core into cell membranes are ultrasonic treatment which are all used to fabricate CMCNs. and membrane extrusion [84, 85]. Sonication has been employed to fuse the PLGA core into the platelet mem- Procedures for engineering CMCNs brane, which exhibits various “self-recognized” proteins Preparation of CMCNs [86]. The duration, power, and frequency of the sonica - The preparation of CMCNs can be processed through tion should be adjusted to minimize drug leakage and four major steps. The first step is to separate the mem - protein denaturation and enhance fusion efficiency. In branes from the parent cells by using a hypotonic buffer membrane extrusion, membranes are extruded using a Fig. 2 The preparation of cell membrane-coated nanocarriers is a multistep process. Cell membranes are typically synthesized in three steps: cell lysis, membrane separation, and extrusion to obtain homogenous cell membrane vesicles Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 8 of 21 technique known as sequential extrusion. In this tech- the biosynthesis of certain proteins using the parental nique, samples (a mixture of core nanoparticles and cell protein machinery. membrane) are extruded through different-sized pores. Pre-modification approach results in a more homog - It is crucial to control the nanoparticle-to-cell membrane enous and secure source of membrane, but the types of ratio in order to ensure complete surface coverage for ligand and component possibilities are inadequate as both of these techniques [87]. A new microfluidic elec - compared to the post-modification approach. Several troporation-based procedure has recently been devel- post-modification methods have been developed due to oped to apply a full membrane coating on the inner core, the availability of divers and convenience modified mate - which means that different factors, such as flow veloc - rials. The materials used for modification range from nat - ity, duration, and voltage, must be tailored to meet the ural lipids [94], nucleic acids [95], and proteins [96], to desired results [88]. synthetic components [97]. Cholesterol is one lipid that is used to modify vesicles derived from cell membranes for CMCNs. It plays an important role in the formation Modification of cell membrane of the cell membrane’s lipid bilayer structure. Changes The structure, functions, and components of cell mem - in cholesterol ratios can affect the rigidity and fluidity of branes have become more understandable as cell biology membranes [98]. The addition of cholesterol increases progresses [89]. The composition of the cell membrane is the stability of vesicles derived from cell membranes in mainly composed of a lipid bilayer, while protein and car- terms of their resistance to environmental pH changes bohydrate molecules are lodged in the hydrophobic part [94]. In the case of RBCs, adding cholesterol to RBCs and of the lipid layer [90]. One of the major functions of the slightly heating them for 10 min increased the rigidity of cell membrane is to protect the intracellular organelles, their vesicles, significantly improving the efficacy of drug which transport nutrients, process waste, and regulate loading. Proteins can be conjugated to the cell mem- metabolism. Moreover, cell-to-cell contacting signal- brane through insertion or conjugation. For instance, a ing is also regulated by the cell membrane. Therefore, bifunctional linker functionalized with N-hydroxysuc- the cell membrane can be modified for desirable func - cinimide at one end and maleimide at another terminal tions. The modification of the cell membrane may be was used to conjugate hyaluronidase to the RBC mem- processed either before disrupting the parent cells (i.e., brane [96]. Another study used an amphiphilic lipid pre-modification) or additional components are subse - to anchor protein to the surface of a membrane vesicle quently introduced into membranes after isolation (i.e., [97]. In this approach, streptavidin was first attached post-modification). to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- In pre-modification, the properties of the parent cell N-[maleimide (polyethylene glycol)-2000] and then the membrane are modified at metabolic or genetic levels. lipid tail was inserted into the cell membrane. Inserting a Parent cells are treated with certain chemical or physi- protein-conjugated lipid into the cell membrane enables cal stresses to induce the expression of specific lipid or protein affixing without disturbing membrane surface protein components, or to modify the structure of mem- proteins, thereby increasing the likelihood of membrane brane hydrocarbon chains [91]. Metabolic glycosylation proteins retaining their intact structure. However, chemi- is mainly used to control expression levels of native gly- cal conjugation of lipid moieties with a protein may alter cans, but it can also be used to introduce artificial mono - the configuration of associated proteins. Strategies for saccharides into glycol-conjugates [92]. RBCs are one of conjugating proteins with lipid moieties at specific sites the most frequently used sources for generating vesicles must be carefully designed to minimize possible configu - derived from cell membranes. However, it is impossible rational changes. Another substance used to modify the to modify mature RBCs genetically due to the absence vesicles derived from the cell membrane is nucleic acids. of nuclei in mature RBCs. To overcome this problem, Lv Aptamers are short single-strand oligonucleotides that et al. used the CRISPR gene-editing strategy to engineer may precisely attach to a target substrate. Peng et al. used an RBC membrane expressing the tripeptide Asn-Gly- the 26-mer G-quadruplex oligonucleotide AS1411, which Arg (NGR) [93]. Transgenic mice were generated in this binds to nucleolin, to modify the membrane of cancer study by inserting NRG peptide coding in the pre-embryo cells [95]. The AS1411 aptamer enabled tumor-targeting stage. A genetic analysis of newborn mice was used to of membrane vesicles because of the overexpression of validate the NGR expression. RBCs were isolated from nucleolin in tumor tissue (Fig. 3). these mice and used to generate RBC membrane vesicles It is well known that synthetic polymers, particularly for targeted delivery of an oncolytic virus to tumors. As PEG, have been used to modify cell membrane for the exogenous physical or chemical coupling onto vesicles preparation of CMCNs [99, 100]. By protecting CMCNs may alter protein function, so genetic engineering allows from phagocytosis, PEG conjugation increases their L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 9 of 21 Fig. 3 Post-modification of cell membrane. Cell membranes can be modified with different molecules or biomarkers to modulate their biological behaviors. An illustration of aptamers (A), protein (B), cholesterol (C), and synthetic polymer (D) conjugated cell membrane colloidal stability and thus their circulation half-life example, RBC membrane-coated nanocarriers can avoid in vivo. PEGylation can be accomplished merely through reticuloendothelial clearance because they express CD47 the incubating PEG lipid derivatives and cell membrane (immunoregulatory marker) [103]. Similarly, P-selectin at 37 °C. PEG lipid tails easily insert into membrane lay- is a ligand of the CD44 receptor found in platelet mem- ers in these conditions. One issue with current PEGyla- branes, allowing it to be targeted at cancer cells [104]. tion methods for membrane vesicles is the lack of These membranes can be used to coat nanocarriers to precise quantification. The outcome of PEGylation may improve drug delivery efficiency. It was discovered that be dependent on the compactness of PEG on the vesicles. PLGA nanocarriers coated with RBC-platelet mem- As a next step, researchers should establish standard pro- brane have a longer blood circulation time and better cedures for PEGylation of the cell membrane. binding to MDA-MB231 breast cancer cells than plain PLGA nanoparticles [103]. Another study used homo- Cell membrane hybridization typic targeting by fusing cancer cell membranes with It is possible to create a hybrid cell membrane by fus- RBC membranes [105]. The hybridized MCF7-RBC ing two parent cell membranes. These cell membranes membrane-coated nanocarriers were found to be highly have both parental cell membrane properties. Hybrid effective in terms of photothermal effect and accumula - cell membranes can synergistically carry out complex tion at tumor site in MCF7 tumor-bearing mice. This behaviors. Several studies have used hybrid cell mem- study established that the protein proportion of dual branes to coat synthetic nanocarriers [101, 102]. For membranes was a significant predictor of homotypic Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 10 of 21 impact and blood retention. To achieve the best perfor- cancer [117]. Plain mesoporous nanocarriers have a short mance, the ideal proportion of the two membranes must half-life and nonspecific macrophage uptake. To fight be found empirically. Not only may hybrid membranes be against cancer, the RBC membrane coating decreases formed by fusing two cell membranes together, but they non-specific uptake and increases blood circulation time can also be formed by fusing a cell membrane and a lipo- while combining phototherapeutic and chemotherapeu- some together. Pitchaimani et  al. reported a nanocarrier tic effects (Fig. 4). coated with a hybridized membrane of the natural killer Modification of RBC membranes with specific ligands cell membranes and liposomes [106]. The hybridization can improve delivery to target tissues. For example, when of liposome membranes in this approach enables the RGDyK peptide was inserted into the RBC membrane incorporation of several lipid components of liposomes used for coating of drug nanocrystals, they had a bet- into the cell membrane. ter distribution to tumors and antitumor efficacy than nanocrystals coated with unmodified RBC membrane or Pure cell membrane used in nanocarrier coating plain nanocrystals [97]. The CDX peptide derived from Red blood cells the neurotoxin was also used for the modification of RBC RBCs have attracted considerable interest as a biomate- membranes to target brain tissues [115]. The CDX pep - rial for nanocarriers coating [83]. In humans, RBCs have a tide was anchored to RBC membranes by streptavidin– short lifespan of up to 120 days. This short-lived property biotin. In a glioma mouse model, CDX peptide added of RBCs makes them an excellent source of membrane for to RBC membranes increased brain delivery. Zhou et al. coating nanocarriers. RBCs have a significant role in the chemically rooted hyaluronidase onto the surface of RBC removal of pathogens from the body via oxycytosis dur- membranes via bifunctional linker succinimidyl-[(N- ing the transportation of oxygen [107]. RBCs also express maleimidopropionamido)-polyethyleneglycol] ester to the ‘don’t eat me’ marker CD47, which binds to the improve tissue penetration [96]. The modification of RBC macrophage-expressed signal-regulatory protein α pre- membranes did not affect their pharmacokinetics and venting it from being taken up [108]. Therefore, the use hyaluronidase also showed its activity as usual. of an RBC membrane to coat the nanocarrier improves the detoxification process, the removal of pathogens, White blood cells and long-term circulation. Because of these properties, White blood cells (WBCs) are colorless, nucleated spher- the RBC membrane can be used for coating a variety of ical blood cells that influence disease progression. Nano - nanocarriers to deliver drugs targeting breast cancer carriers surface engineered with a WBC membrane have and colon cancer [108–111]. However, RBC membrane been widely used as anticancer drug carriers in recent can also be functionalized with iRGD peptide and folate years due to their immune escape and active targeting receptor to target breast cancer [112, 113]. For targeting abilities [118]. The most used WBCs for surface engineer - the brain, targeting ligands such as T7, cRGD peptide, ing of nanocarriers are neutrophils and macrophages. CDX peptide, and NGR peptide are incorporated into Neutrophils are the first immune cells to respond to the RBC membrane [97, 114, 115]. Coating nanocarriers tumours or infection and are closely linked to tumor pro- taking in anticancer drugs, photodynamic or photother- gression, making them ideal carriers of antitumor drugs. mal agents with RBC membranes can be used to address They are activated by chemokines or cytokines like inter - the problem of short blood retention time. Recently, a feron-gamma, interleukin 8, granulocyte–macrophage study reported melanin nanocarriers coated with RBC colony-stimulating factor, and tumour necrosis factor α membrane for effective photothermal cancer therapy which direct them to the inflammation or infection site [116]. They observed that melanin nanocarriers coated [119]. It has been shown that conformational variations with RBC membrane had higher photo thermal efficacy in integrins such as L-selectin, P-selectin, macrophage-1 in  vivo than bare melanin nanocarriers due to improved antigen, LFA-1, and VLA-4 also support neutrophil blood retention and tumor site accumulation. RBC mem- mobilization via extravasation from blood vessels [120]. branes have also been coated on iron oxide nanomaterials Therefore, the neutrophil membrane can be used for sur - capable of photothermal conversion [111]. The iron oxide face engineering of nanocarriers to target breast cancer, clusters coated with RBC membrane retain their pho- circulating tumour cells, lung cancer, and premetastatic tothermal properties while being less absorbed by mac- niches [25, 50, 121]. Zhao et  al. reported a biomimetic rophages. After intravenous injection, iron oxide clusters nanocarrier (PTX-CL/NEs) prepared by coating PTX- coated with RBC membrane showed less liver distribu- loaded liposomes with neutrophil membranes [122]. tion and more tumor accumulation in mice. Mesoporous PTX-CL/NEs successfully target tumor sites, release nanocarriers encapsulating doxorubicin have also been drugs, and inhibit tumor growth and recurrence. Cao coated with RBC membranes for photochemotherapy of et  al. surface engineered Celastrol-loaded PEG-PLGA L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 11 of 21 Fig. 4 a Curves of tumor volume in A549 tumor-bearing mice treated with various agents. b Curves of body weight of mice in each group. c Images of tumors dissected on the 13th day following photothermal treatment, as well as a comparison of each group’s tumor weight. d Hematoxylin and eosin staining images of major organs and tumor tissues dissected on the 13th day following photothermal treatment. Reproduced with permission from [116] Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 12 of 21 nanocarriers with neutrophil membranes [123]. Coating atherosclerotic sites by platelet membrane-coated nano- with neutrophil membranes allowed nanocarriers to pick carriers. So, platelet membrane coating enables nanocar- up by chemokines, pass through the blood-pancreas bar- riers to escape from macrophages and selectively bind rier, and reach the tumor site. Although neutrophil mem- injured vessels and tumour tissues. Because of these branes are rich in targeting content and fast to pick up properties, platelet membrane coated nanocarriers can by chemokines, they are preferred to use in acute treat- be used to target breast cancer lung metastasis and cir- ment situations [124]. In the case of allogeneic blood as culating tumour cells [57, 75]. When using nanocarriers a source of WBC membranes, infectious disease screen- coated with platelet membranes, it is suggested to focus ing and blood type compatibility are required because the on CD47 receptor integrity. A functional change in the WBCs are extremely diverse [125] (Fig. 5). CD47 receptor may affect biodistribution and pharma - Macrophages are classified as M1 or M2 depending on cokinetics of nanocarriers. Nanocarriers coated with their activation state. M2 macrophages reduce inflamma - platelet membranes should not be used in patients with tion, suppress the immune system, and promote tumour autoimmune diseases. Platelet autoantibodies may form growth, whereas M1 macrophages cause inflammation, immune complexes with nanocarriers [131]. stimulate the immune system, and extinguish tumour tis- In recent years, the number of platelet membrane sue [126]. M1 macrophages’ antitumor effect is derived coated drug delivery systems has increased rapidly due from surface markers like CD86, CD80, and MHC-II. to their easy extraction, purification, and accumulation Therefore, macrophage membrane-coated nanocarriers at cancer sites [132]. Rong et  al. reported a nanocarrier have been widely employed for developing antitumour of platelet membrane coated black phosphorus quantum nanocarriers targeting breast cancer and lung metas- dots carrying hederagenin (PLT@BPQDsHED) [133]. tasis of breast cancer [22, 35, 127]. The microenviron - PLT@BPQDs-HED had a stronger fluorescence signal at ment of cancer affects macrophages, so their antitumor the cancer site and a higher retention rate than the con- effect is often enhanced by administrating macrophages trol group after 48  h. A higher efficiency of drug deliv - with other therapies. Hu et  al. synthesized biomimetic ery is achieved by PLT@BPQDs-HED because selectin nanocarriers [(C/I)BP@B-A(D)&M1m] that were encap- on the platelet membrane specifically attaches to the sulated in the M1 macrophage membrane [128]. Numer- CD44 receptor overexpressed in cancer tissue. Platelets ous molecules involved in over expression of major are much more related to cancer cells, and the nanocar- histocompatibility complex (MHC) and costimulatory riers that are wrapped into platelet membranes avoid signal transduction on the cell membrane enabled (C/I) clearance by the immune system and specifically target BP@B-A(D)&M1m to target cancer tissues effectively. cancer tissue via the proteins on the membrane surface. When combined with laser irradiation, (C/I)BP@B- Platelet membrane-coated drug delivery systems have the A(D)&M1m efficiently released drugs at the site of appli - potential to be used in combination with immunotherapy cation. Liu et  al. synthesized a mixed micelle containing and phototherapy. Wu et al. wrapped nanocarriers com- bilirubin (ROX-responsive) and chlorin e6 (photosen- prising the anticancer drug and polypyrrole into platelet sitizer), loaded with paclitaxel dimer, and wrapped into membranes [134]. Platelet membrane enables the drug a macrophage membrane. By co-delivering paclitaxel delivery system to escape from immune systems and tar- dimer and Ce6, these nanocarriers effectively combine get the cancer tissue, laser irradiation triggers polypyr- photodynamic and chemotherapy therapy. Macrophage role to cause hyperthermia and ablate the cancer cells, membranes can shield drugs from being taken up by and anticancer drugs are also discharged from the nano- macrophages, which increases the likelihood of nanocar- carriers to destroy the cancer tissue. riers being absorbed and retained by tumor cells. Cancer cell Platelet Cancer is described as abnormal cell growth that could Platelets are nucleate cells of blood produced by mega- lead to metastasis. Cancerous cells’ membrane display a karyocyte fragmentation and are involved in tumor variety of tumour-specific adhesion and antigen moieties. metastasis, thrombosis, and blood coagulation [129]. There are a wide range of molecules involved in cell–cell Platelet membranes have the ability to escape phago- and cell–matrix adhesion, such as mucoprotein-1, epi- cytosis in systemic circulation. Like RBCs, the platelet thelial adhesion moieties, lymphocyte-homing recep- membrane has CD47 receptors. CD47 receptors interact tors, galectin-3, integrins, and cadherins [36, 135, 136]. with regulatory proteins that inhibit macrophage recep- Cancer cells possess properties that collectively serve a tors and can affect the pharmacokinetics of encapsu - self-protective function, such as homotypic cell adhesion lated drugs. Platelet glycoproteins may also interact with and immune system evasion [137]. Since these cells have collagen-rich plaque [130], assisting in the targeting of unique characteristics, their membranes have gained L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 13 of 21 Fig. 5 Antitumor efficacy of neutrophil membrane-coated nanocarriers in mice. A Images of mice after i.v. injections of Dil stain, Dil stain loaded PEG-PLGA nanocarriers, neutrophil membrane-coated Dil stain loaded PEG-PLGA nanocarriers. B Images of major organs and tumors after i.v. injections at 24 h, C average tumor volumes following various treatments over time, (D) morphology of tumors after 35 days, (E) variations in body weight, and (F) variations in tumor weight each treatment group over time [123] Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 14 of 21 popularity as coating stuff for nanocarriers. The dis - TGF-b1 and PD-ligand 1 expression in the tumor envi- persed membrane of cancer cells on nanocarriers allows ronment. Furthermore, T cell membrane-coated nano- various characteristics of cancer cells to be introduced to carriers improved dacarbazine delivery and enhanced the nanocarriers for targeting homotypic tumours and apoptosis of tumor cells. Ma et  al. reported the devel- developing personalized cancer therapy [66, 138]. Metal opment of a nanocarrier composed of mesoporous oxide nanoparticles, gelatin particles, mesoporous silica, silica holding IR780 nanoparticles wrapped into the and PLGA nanocarriers have all been wrapped into can- membranes of chimeric antigen receptor T cells (CAR- cer cell membranes and used to deliver anticancer drugs T) to exclusively target hepatocellular carcinoma cells [24, 72, 139, 140]. (HCCs) expressing GPC3 [85]. They engineered the Membranes of cancer cells have the feature of homolo- CAR-T cell nanocarrier in such a way that it could detect gous targeting that can be used for targeting homologous GPC3-expressing HCCs. The results demonstrated that toumors [24]. In this respect, iron oxide nanocarriers NP-coated CAR-T cell membranes were more effective were coated with HeLa cell and UM-SCC-7 membranes. at targeting HCC cells in  vivo and in  vitro than IR780- When these coated nanocarriers were allowed to incu- loaded mesoporous silica. CAR-T cell therapy is a newer bate with HeLa, HepG2, UM-SCC-7, and COS7 cells. The blood cancer treatment. Ex  vivo CAR-T cells are pro- coated nanocarriers showed a high affinity towards HeLa duced by genetically modifying TCR to recognize an cells and UM-SCC-7 cells. They could also self-target a antigen without antigen presentation. Ex  vivo-amplifier homologous tumor and effectively restrain tumor growth CAR-T cells are then reinfused into hematological can- in vivo. Some studies also reported the blood–brain bar- cer patients. The FDA has approved CAR-T cell targeting rier crossing ability of cancer cell membranes [141, 142]. of the CD19 antigen for the treatment of relapsed/refrac- For example, nanoparticles of polycaprolactone/F68 were tory diffuse large B-cell lymphoma or acute lymphoblas - coated with secondary brain cancer cell membranes and tic leukemia. then loaded with indocyanine green, a photothermal and imaging agent [141]. Intravenous injection of these Dendritic cells nanocarriers into mice bearing U87MG-Luc glioma cells Dendritic cells (DCs) are immune cells that gather showed high distribution in the brain. Similarly, PEG- around cancer cells due to immune signals (such as path- PLGA nanocarriers coated with MDA-MB-831 cancer ogen-associated molecular patterns and proinflamma - cell membrane were investigated for use in treating brain tory cytokines). They transfer tumor-associated antigens cancer [142]. They found that the accumulation of coated to lymph nodes to establish communication with naive nanocarriers in the brain was higher than uncoated T cells for differentiation into attack cancer cells and nanocarriers. mature T cells [146]. For this reason, designing tumor immunotherapy around DCs characteristics is a prom- T cells ising approach. However, issues like complex prepara- T cells play an important role in adaptive immune tion methods, short efficacy periods, and high cost still responses [143]. T cells need antigen priming through need to be addressed [147]. DC membranes contain a specific T-cell receptor (TCR) for activation. The den - components like DC-originating molecules and can tar- dritic cells (DCs) possess the MHC-antigen complex get and stimulate the immune systems of their source that engages with the TCR and activates T cells. Acti- cells [148]. It has been shown that CD40/CD80/CD83/ vated naive T cells become regulatory or effector T cells, CD86 are upregulated on the DC membranes as co-stim- depending on the DC-T cell immune synapse context. ulatory receptors [149]. The binding of these molecules Effector T cells scavenge and kill cancerous or virus- to their respective receptors on T-cells activates DCs to infected cells in the bloodstream. Moreover, T cells can produce cytokines such as IL-10, IL-12, and interleukin also mature into memory T cells, which offer long-lasting that distinguish T cells into their anti-inflammatory or protection against foreign bodies that activated them. pro-inflammatory subsets. Therefore, DC membranes Therefore, T cell membranes coated nanocarriers can be coated nanocarriers can be used to target prostate can- used to target gastric cancer, liver cancer, and tumour tis- cer and ovarian cancer [150, 151]. Cheng et  al. reported sues [85, 92, 144]. an IL-2-loaded PLGA nanocarrier warped in membranes T cell membranes were used to wrap PLGA nanocar- derived from DCs [151]. The DCs derived membranes riers loaded with dacarbazine [145]. In this study, T cell provide unique and potent stimulatory signals and sus- membranes were extracted from the EL4 cell line and tain a strong T-cell response due to their intact surface incubated with PLGA nanocarriers loaded with dacar- proteins. The nano-dimensions of this carrier may be a bazine. T cell membrane-coated nanocarriers were able significant contributor to the T cell response by elimi - to bypass tumor immune suppression and neutralize nating spatial barriers throughout antigen presentation. L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 15 of 21 Zhang et  al. used a combination of a nanocarrier-based He et al. joined a leukocyte membrane with a cancer cell antigen delivery system and photochemical internaliza- membrane to increase the targeting potential of HMCNs. tion to induce tumor-specific cytotoxic T cells in their The leutusome was produced by fusing together the study [152]. It was demonstrated that the combination membranes of leukocytes, tumor cells, and liposomal of a hydrophobic photosensitizer (Pheophorbide A) and nanocarriers simultaneously [157]. Encapsulation of polyethyleneimine possessed the ability to evade endoso- paclitaxel (PTX) with leutusomes significantly  reduced mal degradation while also enabling near-infrared imag- tumor development without causing systemic damage ing. Moreover, by grafting the synthesized complex onto (in vivo), suggesting that selective taken up of leutusomes ovalbumin, a model antigen, light-sensitive nanocarriers by tumor cells. After 48  h, leutusomes labeled with DIR were formed. displayed substantial fluorescence in tumor sites that were 9.3-fold larger than those in the control. The lipo - Hybrid membrane used in nanocarrier coating somal NPs accumulation from leukocytes or cancer cells Hybrid membranes can be used to combine the prop- was 2.7-fold and 4.4-fold more in the tumor, respectively, erties of a variety of cell membranes and optimize their than in the control. Additionally, the study indicated function [101]. In general, hybrid membrane coated that coating outside of the cores or incorporation into nanocarriers (HMCNs) more specifically interact with liposomal nanocarriers had no effect on the unique fea - the cancer environment, resulting in improved specific tures of different cell membranes. These composite bio - targeting, minimizing non-specific interactions with mimetic nanocarriers outperform solid tumour homing abundant proteins and cellular components, and opti- and have a longer circulation time due to surface markers mizing specific biological roles [153]. Moreover, a hybrid expressed on both cell types. membrane incorporates at least two distinct biological Sun et  al. developed a cancer cell-RBC hybrid mem- activities. One is a competence for targeting, whereas brane coated gold nanocage loaded with doxorubicin the other refers to inherent properties conferred by the to treat breast cancer via chemotherapy, photothermal membranes of a source cell. The targeting potential is therapy, and radiotherapy [158]. Homological targeting primarily comprised of homologous targeted delivery of the cancer cell membrane and reduced clearance by to tumor sites via DC membranes and cancer cell mem- the RBC membrane made the HMCNs particularly effec - branes, specific tumor targeting via PLT membranes, the tive in accumulating in tumor sites. Macrophages have capability of tumor targeting enhancement via mem- been associated with the early dispersion of cancer and branes of stem cells, and circulating tumor cells target- hence have a substantial effect on prolonging metastasis ing via WBC and PLT membranes [75, 154–156]. The throughout the progression of cancer. Gong et  al. devel- latter biological function types mainly include prolonga- oped a hybrid membrane composed of macrophages and tion of blood circulation via PLT and RBC membranes; cancer cells coated with doxorubicin-loaded PLGA nano- specific adherence to injured vessels via PLT membranes; carriers for use in breast cancer treatment to specifically immune evasion via PLT and WBC membranes; toxin target lung metastases [159]. Since RAW264.7 membrane neutralization and absorption via RBC and macrophage exhibits enhanced expression of high integrin α4β1, the membranes; and activation of the immune system via resultant HMCNs demonstrate remarkable membrane- bacterial outer membranes, cancer cell membranes and derived features, which include the capacity to target immune cell membranes. Due to the membrane combi- homologous cancer cells and improved particular meta- nation, HMCNs can achieve maximum functionality in static targeting potential. The metastatic nodule numbers diverse biomedical fields. in the lung were reduced by about 88.9% after the therapy The leukocyte membrane is considered a naturally of lung metastases derived from breast cancer, which occurring coating material with the biomimetic potential, performed better than the pure CMCNs. This hybrid capable of evading immune system capture and inflam - membrane derived platform demonstrates promise as a matory targeting via inducing inflammation via special - biomimetic nanoplatform for the metastasis treatment of ized ligand-receptor interaction [121]. Vectors that are breast cancer. similar to leukocytes could continue their capabilities, He and Su’s group previously described the use of such as inhibiting particle phagocytosis and opsoniza- HMCNs based on RBC and retinal endotheliocyte mem- tion, facilitating the transportation over the endothelial branes for non-invasive therapy of choroidal neovas- layer while avoiding the lysosomal pathway and thereby cularization [160]. The RBC and retinal endotheliocyte delaying the clearance by the liver [27]. However, a drug membranes fusion provide protection to the nanocar- delivery system based on a single leukocyte membrane rier against phagocytosis while also giving the potential is incapable of achieving adequate therapeutic efficiency to the HMCNs to bind with vascular endothelial growth because of its incapability towards tumor targeting. Thus, factors, enhancing their potential to target choroidal Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 16 of 21 neovascularization regions actively. particularly, the anti- biocompatibility. Platelet membranes are highly sensi- VE-cadherin antibody suppressed the fluorescent signals tive, so finding an appropriate loading scheme to ensure in HMCNs-treated cells, demonstrating that the ability of adequate drug loading and reliable delivery to the target self-targeting is dependent on surface binding molecules tissue is challenging. The toxicity and stability of modi - (N- and VE-cadherin) expression on the retinal endo- fied membranes must also be studied, especially as nano - theliocyte membrane [161]. The substantial fluorescence carriers for cancer therapy. To achieve the desired dose colocalization of angiogenic retinal endotheliocyte mem- and release profile, the drug loading method should be branes and HMCNs in the tube formation experiment chosen carefully [163]. also indicated the nanocarriers’ targeting ability. Fur- Moreover, a complete understanding of the mecha- thermore, using a quantitative examination of the mean nism of transporting cell membranes extracted from dif- fluorescence intensity, the group treated with HMCNs ferent sources in  vivo is unknown and requires further drastically decreased damage area and choroidal neovas- research. For example, therapeutic molecules delivered cularization leakage in contrast to the group treated with by white cell membrane carriers may activate immune pure CMCNs in a choroidal neovascularization mouse system components and cause inflammation [164]. When model induced by laser. In conclusion, dual-fused mem- cancer cell membrane is used, it may cause cancer in the brane-based nanocarriers offer significant advantages body if the parent cancer cells’ genetic material is not over currently available invasive therapies. completely removed. Procedures for purifying and char- acterizing cell membranes are not consistent and differ Challenges and future directions from laboratory to laboratory, causing confusion about Numerous advantages have been reported for CMCNs, the physicochemical features of the cell membrane. So, particularly in terms of biocompatibility and targeting. it is necessary to share the scientific data and develop a Synthetic DDSs currently available are basically foreign standardized procedure for cell membrane quality con- substances with the potential for immunogenicity and trol that is highly repeatable. Nanocarriers wrapped into toxicity. Whereas cell membranes are endogenous, they cell membranes and extracellular vesicles can target can- are considered biocompatible and perform a variety of cer tissues crossing biological barriers. Some cells can be biological functions like the source cell. However, cer- used to both extract membranes and isolate extracellular tain issues must be resolved before these carriers can vesicles to transport drugs. While it is relatively simple continue to evolve and move from the laboratory to the to extract and prepare the cell membrane, the targeting clinic. ability may be compromised due to protein loss during The first and most important question to be addressed membrane extraction. However, extracellular vesicles is about the yield of cell membranes and extracellu- are difficult to prepare, they generally retain all mem - lar vesicles. Not only do existing separation technolo- brane components, giving them excellent targeting ability gies produce a negligible amount of cell membranes [165]. As a result, the appropriate carrier must be chosen and extracellular vesicles, but they are also prohibitively according to the experiment’s objective in order to maxi- expensive for large-scale production. As a result, more mize the therapeutic effect. sophisticated large-scale manufacturing methods are required to continue expanding the application of cell Conclusions membrane. In recent years, to address the yield issue, The development of therapeutics derived from cell extensive work has been carried out on techniques membrane material is a rapidly growing field of which are used for generating artificial vesicles when research that is particularly appealing because it the membrane is ruptured via extrusion. For example, involves an organic cellular networking system. Biomi- the same number of THP-1 cells yield more than twice metic technology has the advantage of taking advan- as many simulated exosomes as natural exosomes, and tage of the natural mechanisms of living matter, but the drug encapsulating and releasing rates of the simu- it is also a double-edged sword. It is difficult to know lated exosomes are also higher [162]. The extraction which components, out of the multiple factors, confer and purification procedures must also be revised and membrane functionality, and so the ratio of each com- optimized, as many cells must still be cultured to obtain ponent needs to be modified as needed. To develop an adequate number of membranes, and the prepara- drug-containing membrane-coated carriers, a simi- tion procedure must still be simplified [118]. For RBCs larly and standardized manufacturing process will be membrane-coated nanocarriers that lack a targeting abil- required. Despite the difficulties associated with pro - ity, the membranes must be modified to reach the tar - cessing variables, manufacturing, and quality control, get site for therapeutic cargo release, but this will likely vesicles derived from natural cells have the advantage change the membrane’s original structure and reduce its of being bioactive, reflecting the features of the parent L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 17 of 21 3. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocar- cells. Although membrane-coated nanocarriers face riers as an emerging platform for cancer therapy. Nat Nanotechnol. numerous challenges, a powerful advantage of ‘mimick- 2007;2:751–60. ing nature’ overrides many disadvantages of traditional 4. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in adminis- tering biopharmaceuticals: formulation and delivery strategies. Nat Rev DDSs and offers a more efficient approach for cancer Drug Discov. 2014;13:655–72. treatment. With the rapid advancement of nanotech- 5. Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: nology, proteomics, bioinformatics, pharmacology, and passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Contr Rel. 2010;148:135–46. material science, it is expected that the combination 6. Ekladious I, Colson YL, Grinstaff MW. Polymer–drug conjugate of DDSs and cells will overcome numerous obstacles, therapeutics: advances, insights and prospects. Nat Rev Drug Discov. revolutionize current medical technology, and open up 2019;18:273–94. 7. Zhou M, Huang H, Wang D, Lu H, Chen J, Chai Z, Yao SQ, Hu Y. Light- new avenues for targeted cancer therapy. triggered PEGylation/dePEGylation of the nanocarriers for enhanced tumor penetration. Nano Lett. 2019;19:3671–5. Acknowledgements 8. Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to Authors are grateful to Hospital of Hangzhou Medical College for providing clinical applications. Adv Drug Deliv Rev. 2013;65:36–48. necessary facilities. 9. Moradi Kashkooli F, Soltani M, Souri M. Controlled anti-cancer drug release through advanced nano-drug delivery systems: static and Authors’ contributions dynamic targeting strategies. J Contr Rel. 2020;327:316–49. WL, CY, YW, GR, XH, XT, and SW wrote different sections of the manuscript. WL, 10. Shreffler JW, Pullan JE, Dailey KM, Mallik S, Brooks AE. Overcoming hur - CY, and SW edited the manuscript. All authors read and approved the final dles in nanoparticle clinical translation: the influence of experimental manuscript. design and surface modification. Int J Mol Sci. 2019;20:6056. 11. Walsh G. Biopharmaceutical benchmarks 2018. Nat Biotechnol. Funding 2018;36:1136–45. This study was supported by the Foundation of Science Technology Depart- 12. DeLoach J, Barton C, Culler K. Preparation of resealed carrier erythro- ment of Zhejiang Province (No. LGF22H080012, LY19H160037, LGF18H160025) cytes and in vivo survival in dogs. Am J Vet Res. 1981;42:667–9. and the funds from Zhejiang Medical Technology Plan Project (No. 13. Pang L, Zhang C, Qin J, Han L, Li R, Hong C, He H, Wang J. A novel strat- 2020KY052). egy to achieve effective drug delivery: exploit cells as carrier combined with nanoparticles. Drug Deliv. 2017;24:83–91. Availability of data and materials 14. Jiang X, Rocker C, Hafner M, Brandholt S, Dorlich RM, Nienhaus GU. Not applicable. Endo-and exocytosis of zwitterionic quantum dot nanoparticles by live HeLa cells. ACS Nano. 2010;4:6787–97. Declarations 15. Hu C-MJ, Zhang L, Aryal S, Cheung C, Fang RH, Zhang L. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic Ethics approval and consent to participate delivery platform. Proc Nat Acad Sci. 2011;108:10980–5. Not applicable. 16. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular Consent for publication drug targeting. Adv Enzyme Regul. 2001;41:189–207. All authors have approved the final draft of this manuscript for submission and 17. Sabu C, Rejo C, Kotta S, Pramod K. Bioinspired and biomimetic systems have given consent for the publication of identifiable details. for advanced drug and gene delivery. J Contr Rel. 2018;287:142–55. 18. Rasheed T, Nabeel F, Raza A, Bilal M, Iqbal H. Biomimetic nanostruc- Competing interests tures/cues as drug delivery systems: a review. Mater Today Chem. The authors have declared no conflict of interest. 2019;13:147–57. 19. Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune responses to viral Author details gene therapy vectors. Mol Ther. 2020;28:709–22. Department of Hematology, The Second Affiliated Hospital, College 20. von Roemeling C, Jiang W, Chan CK, Weissman IL, Kim BY. Breaking of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, People’s down the barriers to precision cancer nanomedicine. Trends Biotech- Republic of China. Department of Ultrasonography, Zhejiang Provincial nol. 2017;35:159–71. People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 21. Gao M, Liang C, Song X, Chen Q, Jin Q, Wang C, Liu Z. Erythrocyte- Zhejiang 310014, People’s Republic of China. Phase I Clinical Research Center, membrane-enveloped perfluorocarbon as nanoscale artificial red Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical blood cells to relieve tumor hypoxia and enhance cancer radiotherapy. College, Hangzhou, Zhejiang 310014, People’s Republic of China. Depar t- Adv Mater. 2017;29:1701429. ments of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital 22. Cao H, Dan Z, He X, Zhang Z, Yu H, Yin Q, Li Y. Liposomes coated with of Hangzhou Medical College, Hangzhou, Zhejiang 310014, People’s Republic isolated macrophage membrane can target lung metastasis of breast of China. Cancer Center, Key Laboratory of Tumor Molecular Diagnosis cancer. ACS Nano. 2016;10:7738–48. and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s 23. Orbach A, Zelig O, Yedgar S, Barshtein G. Biophysical and biochemical Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, markers of red blood cell fragility. Transf Med Hemother. 2017;44:183–7. Zhejiang 310014, People’s Republic of China. 24. Zhu J-Y, Zheng D-W, Zhang M-K, Yu W-Y, Qiu W-X, Hu J-J, Feng J, Zhang X-Z. Preferential cancer cell self-recognition and tumor self-targeting by Received: 22 October 2021 Accepted: 7 January 2022 coating nanoparticles with homotypic cancer cell membranes. Nano Lett. 2016;16:5895–901. 25. Kang T, Zhu Q, Wei D, Feng J, Yao J, Jiang T, Song Q, Wei X, Chen H, Gao X. Nanoparticles coated with neutrophil membranes can effectively treat cancer metastasis. ACS Nano. 2017;11:1397–411. References 26. Spicer JD, McDonald B, Cools-Lartigue JJ, Chow SC, Giannias B, Kubes 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer P, Ferri LE. Neutrophils promote liver metastasis via Mac-1-mediated statistics. CA: Cancer J Clin. 2011;61:69–90. interactions with circulating tumor cells. Can Res. 2012;72:3919–27. 2. Chen W, Zheng R, Zeng H, Zhang S, He J. Annual report on status of 27. Parodi A, Quattrocchi N, Van De Ven AL, Chiappini C, Evangelopoulos cancer in China, 2011. Chin J Cancer Res. 2015;27:2. M, Martinez JO, Brown BS, Khaled SZ, Yazdi IK, Enzo MV. Synthetic Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 18 of 21 nanoparticles functionalized with biomimetic leukocyte membranes 50. Deng G, Sun Z, Li S, Peng X, Li W, Zhou L, Ma Y, Gong P, Cai L. Cell- possess cell-like functions. Nat Nanotechnol. 2013;8:61–8. membrane immunotherapy based on natural killer cell membrane 28. Chugh V, Vijaya Krishna K, Pandit A. Cell membrane-coated mimics: a coated nanoparticles for the effective inhibition of primary and absco - methodological approach for fabrication, characterization for thera- pal tumor growth. ACS Nano. 2018;12:12096–108. peutic applications, and challenges for clinical translation. ACS Nano. 51. An X, Salomao M, Guo X, Gratzer W, Mohandas N. Tropomyosin modu- 2021;15:17080–123. lates erythrocyte membrane stability. Blood. 2007;109:1284–8. 29. Engelman DM. Membranes are more mosaic than fluid. Nature. 52. Chakraborty S, Doktorova M, Molugu TR, Heberle FA, Scott HL, 2005;438:578–80. Dzikovski B, Nagao M, Stingaciu L-R, Standaert RF, Barrera FN. How 30. Bucior I, Scheuring S, Engel A, Burger MM. Carbohydrate–carbohydrate cholesterol stiffens unsaturated lipid membranes. Proc Natl Acad Sci. interaction provides adhesion force and specificity for cellular recogni- 2020;117:21896–905. tion. J Cell Biol. 2004;165:529–37. 53. Virlan MJR, Miricescu D, Radulescu R, Sabliov CM, Totan A, Calenic B, 31. Simons K, Vaz WL. Model systems, lipid rafts, and cell membranes. Annu Greabu M. Organic nanomaterials and their applications in the treat- Rev Biophys Biomol Struct. 2004;33:269–95. ment of oral diseases. Molecules. 2016;21:207. 32. Casares D, Escribá PV, Rosselló CA. Membrane lipid composition: effect 54. Anselmo AC, Mitragotri S. A review of clinical translation of inorganic on membrane and organelle structure, function and compartmentali- nanoparticles. AAPS J. 2015;17:1041–54. zation and therapeutic avenues. Int J Mol Sci. 2019;20:2167. 55. Ehlerding EB, Chen F, Cai W. Biodegradable and renal clearable inor- 33. Kim J, Koo B-K, Knoblich JA. Human organoids: model systems for ganic nanoparticles. Adv Sci. 2016;3:1500223. human biology and medicine. Nat Rev Mol Cell Biol. 2020;21:571–84. 56. Su S, Kang PM. Systemic review of biodegradable nanomaterials in 34. Andrews RK, López J, Berndt MC. Molecular mechanisms of platelet nanomedicine. Nanomaterials. 2020;10:656. adhesion and activation. Int J Biochem Cell Biol. 1997;29:91–105. 57. Ye H, Wang K, Wang M, Liu R, Song H, Li N, Lu Q, Zhang W, Du Y, Yang W. 35. Si J, Shao S, Shen Y, Wang K. Macrophages as active nanocarri- Bioinspired nanoplatelets for chemo-photothermal therapy of breast ers for targeted early and adjuvant cancer chemotherapy. Small. cancer metastasis inhibition. Biomaterials. 2019;206:1–12. 2016;12:5108–19. 58. Xu C, Liu W, Hu Y, Li W, Di W. Bioinspired tumor-homing nanoplatform 36. Sökeland G, Schumacher U. The functional role of integrins during for co-delivery of paclitaxel and siRNA-E7 to HPV-related cervical malig- intra-and extravasation within the metastatic cascade. Mol Cancer. nancies for synergistic therapy. Theranostics. 2020;10:3325. 2019;18:1–19. 59. Zhang Q, Dehaini D, Zhang Y, Zhou J, Chen X, Zhang L, Fang RH, Gao W, 37. Bose RJ, Paulmurugan R, Moon J, Lee S-H, Park H. Cell membrane- Zhang L. Neutrophil membrane-coated nanoparticles inhibit synovial coated nanocarriers: the emerging targeted delivery system for cancer inflammation and alleviate joint damage in inflammatory arthritis. Nat theranostics. Drug Discov Today. 2018;23:891–9. Nanotechnol. 2018;13:1182–90. 38. Evangelopoulos M, Parodi A, Martinez JO, Yazdi IK, Cevenini A, van de 60. Tang J, Shen D, Caranasos TG, Wang Z, Vandergriff AC, Allen TA, Hensley Ven AL, Quattrocchi N, Boada C, Taghipour N, Corbo C. Cell source MT, Dinh P-U, Cores J, Li T-S. Therapeutic microparticles functionalized determines the immunological impact of biomimetic nanoparticles. with biomimetic cardiac stem cell membranes and secretome. Nat Biomaterials. 2016;82:168–77. Commun. 2017;8:1–9. 39. Kaneti L, Bronshtein T, Malkah Dayan N, Kovregina I, Letko Khait N, 61. Li L-L, Xu J-H, Qi G-B, Zhao X, Yu F, Wang H. Core–shell supramolecular Lupu-Haber Y, Fliman M, Schoen BW, Kaneti G, Machluf M. Nanoghosts gelatin nanoparticles for adaptive and “on-demand” antibiotic delivery. as a novel natural nonviral gene delivery platform safely targeting ACS Nano. 2014;8:4975–83. multiple cancers. Nano Lett. 2016;16:1574–82. 62. Gao C, Lin Z, Jurado-Sánchez B, Lin X, Wu Z, He Q. Stem cell membrane- 40. Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ. Therapeutic cell coated nanogels for highly efficient in vivo tumor targeted drug engineering with surface-conjugated synthetic nanoparticles. Nat Med. delivery. Small. 2016;12:4056–62. 2010;16:1035–41. 63. Zhai Y, Ran W, Su J, Lang T, Meng J, Wang G, Zhang P, Li Y. Traceable 41. Van Deun J, Roux Q, Deville S, Van Acker T, Rappu P, Miinalainen I, Heino bioinspired nanoparticle for the treatment of metastatic breast cancer J, Vanhaecke F, De Geest BG, De Wever O. Feasibility of mechanical via NIR-trigged intracellular delivery of methylene blue and cisplatin. extrusion to coat nanoparticles with extracellular vesicle membranes. Adv Mater. 2018;30:1802378. Cells. 2020;9:1797. 64. Rao L, Wang W, Meng Q-F, Tian M, Cai B, Wang Y, Li A, Zan M, Xiao F, Bu 42. Parrow NL, Violet P-C, Tu H, Nichols J, Pittman CA, Fitzhugh C, Fleming L-L. A biomimetic nanodecoy traps Zika virus to prevent viral infection RE, Mohandas N, Tisdale JF, Levine M. Measuring deformability and and fetal microcephaly development. Nano Lett. 2018;19:2215–22. red cell heterogeneity in blood by ektacytometry. J Vis Exp JoVE. 65. Xie J, Shen Q, Huang K, Zheng T, Cheng L, Zhang Z, Yu Y, Liao G, Wang X, 2018;2018:56910. Li C. Oriented assembly of cell-mimicking nanoparticles via a molecular 43. Kuo Y-C, Wu H-C, Hoang D, Bentley WE, D’Souza WD, Raghavan SR. Col- affinity strategy for targeted drug delivery. ACS Nano. 2019;13:5268–77. loidal properties of nanoerythrosomes derived from bovine red blood 66. Nie D, Dai Z, Li J, Yang Y, Xi Z, Wang J, Zhang W, Qian K, Guo S, Zhu C. cells. Langmuir. 2016;32:171–9. Cancer-cell-membrane-coated nanoparticles with a yolk–shell struc- 44. Kim DS, Lee MW, Ko YJ, Jang IK, Jeon S, Na B, Chae JJ, Sung KW, Koo HH, ture augment cancer chemotherapy. Nano Lett. 2019;20:936–46. Yoo KH. Eec ff t of ex vivo culture density on CXCR7 expression in human 67. Castro CI, Briceno JC. Perfluorocarbon-based oxygen carriers: review of mesenchymal stem cells. Int J Clin Exp Med. 2016;9:10802–10. products and trials. Artif Organs. 2010;34:622–34. 45. Park JS, Suryaprakash S, Lao Y-H, Leong KW. Engineering mesenchy- 68. Zou MZ, Liu WL, Gao F, Bai XF, Chen HS, Zeng X, Zhang XZ. Artificial nat - mal stem cells for regenerative medicine and drug delivery. Methods. ural killer cells for specific tumor inhibition and renegade macrophage 2015;84:3–16. re-education. Adv Mater. 2019;31:1904495. 46. Muzykantov VR, Murciano JC, Taylor RP, Atochina EN, Herraez A. Regula- 69. Watermann A, Brieger J. Mesoporous silica nanoparticles as drug deliv- tion of the complement-mediated elimination of red blood cells modi- ery vehicles in cancer. Nanomaterials. 2017;7:189. fied with biotin and streptavidin. Anal Biochem. 1996;241:109–19. 70. Jafari S, Derakhshankhah H, Alaei L, Fattahi A, Varnamkhasti BS, Saboury 47. Wang Y, Zhang K, Qin X, Li T, Qiu J, Yin T, Huang J, McGinty S, Pontrelli AA. Mesoporous silica nanoparticles for therapeutic/diagnostic applica- G, Ren J. Biomimetic nanotherapies: red blood cell based core–shell tions. Biomed Pharmacother. 2019;109:1100–11. structured nanocomplexes for atherosclerosis management. Adv Sci. 71. Xuan M, Shao J, Zhao J, Li Q, Dai L, Li J. Cover picture: magnetic 2019;6:1900172. mesoporous silica nanoparticles cloaked by red blood cell mem- 48. Hu C-MJ, Fang RH, Wang K-C, Luk BT, Thamphiwatana S, Dehaini D, branes: applications in cancer therapy. Angew Chem Int Ed. Nguyen P, Angsantikul P, Wen CH, Kroll AV. Nanoparticle biointerfacing 2018;57:5955–5955. by platelet membrane cloaking. Nature. 2015;526:118–21. 72. Cai D, Liu L, Han C, Ma X, Qian J, Zhou J, Zhu W. Cancer cell membrane- 49. Thamphiwatana S, Angsantikul P, Escajadillo T, Zhang Q, Olson J, Luk coated mesoporous silica loaded with superparamagnetic ferroferric BT, Zhang S, Fang RH, Gao W, Nizet V. Macrophage-like nanoparticles oxide and Paclitaxel for the combination of Chemo/Magnetocaloric concurrently absorbing endotoxins and proinflammatory cytokines for therapy on MDA-MB-231 cells. Sci Rep. 2019;9:1–10. sepsis management. Proc Natl Acad Sci. 2017;114:11488–93. L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 19 of 21 73. Hao N, Yang H, Li L, Li L, Tang F. The shape effect of mesoporous silica therapeutics into cholesterol-enriched cell-membrane-derived vesicles. nanoparticles on intracellular reactive oxygen species in A375 cells. Angew Chem Int Ed. 2017;56:14075–9. New J Chem. 2014;38:4258–66. 95. Peng L-H, Zhang Y-H, Han L-J, Zhang C-Z, Wu J-H, Wang X-R, Gao J-Q, 74. Hu C-MJ, Fang RH, Copp J, Luk BT, Zhang L. A biomimetic nanosponge Mao Z-W. Cell membrane capsules for encapsulation of chemothera- that absorbs pore-forming toxins. Nat Nanotechnol. 2013;8:336–40. peutic and cancer cell targeting in vivo. ACS Appl Mater Interfaces. 75. Li J, Ai Y, Wang L, Bu P, Sharkey CC, Wu Q, Wun B, Roy S, Shen X, King 2015;7:18628–37. MR. Targeted drug delivery to circulating tumor cells via platelet 96. Zhou H, Fan Z, Lemons PK, Cheng H. A facile approach to functionalize membrane-functionalized particles. Biomaterials. 2016;76:52–65. cell membrane-coated nanoparticles. Theranostics. 2016;6:1012. 76. Meng Q-F, Rao L, Zan M, Chen M, Yu G-T, Wei X, Wu Z, Sun Y, Guo 97. Chai Z, Ran D, Lu L, Zhan C, Ruan H, Hu X, Xie C, Jiang K, Li J, Zhou J. S-S, Zhao X-Z. Macrophage membrane-coated iron oxide nanopar- Ligand-modified cell membrane enables the targeted delivery of drug ticles for enhanced photothermal tumor therapy. Nanotechnology. nanocrystals to glioma. ACS Nano. 2019;13:5591–601. 2018;29:134004. 98. Kaddah S, Khreich N, Kaddah F, Charcosset C, Greige-Gerges H. Choles- 77. Lai P-Y, Huang R-Y, Lin S-Y, Lin Y-H, Chang C-W. Biomimetic stem cell terol modulates the liposome membrane fluidity and permeability for a membrane-camouflaged iron oxide nanoparticles for theranostic hydrophilic molecule. Food Chem Toxicol. 2018;113:40–8. applications. RSC Adv. 2015;5:98222–30. 99. Chen Z, Zhao P, Luo Z, Zheng M, Tian H, Gong P, Gao G, Pan H, Liu L, Ma 78. Zhu J, Zhang M, Zheng D, Hong S, Feng J, Zhang X-Z. A universal A. Cancer cell membrane–biomimetic nanoparticles for homologous- approach to render nanomedicine with biological identity derived from targeting dual-modal imaging and photothermal therapy. ACS Nano. cell membranes. Biomacromol. 2018;19:2043–52. 2016;10:10049–57. 79. Cook TR, Zheng Y-R, Stang PJ. Metal–organic frameworks and self- 100. Song Y, Huang Z, Liu X, Pang Z, Chen J, Yang H, Zhang N, Cao Z, Liu M, assembled supramolecular coordination complexes: comparing and Cao J. Platelet membrane-coated nanoparticle-mediated targeting contrasting the design, synthesis, and functionality of metal–organic delivery of Rapamycin blocks atherosclerotic plaque development −/− materials. Chem Rev. 2013;113:734–77. and stabilizes plaque in apolipoprotein E-deficient (ApoE ) mice. 80. Hoop M, Walde CF, Riccò R, Mushtaq F, Terzopoulou A, Chen X-Z, Nanomed Nanotechnol Biol Med. 2019;15:13–24. deMello AJ, Doonan CJ, Falcaro P, Nelson BJ. Biocompatibility charac- 101. Chen H-Y, Deng J, Wang Y, Wu C-Q, Li X, Dai H-W. Hybrid cell mem- teristics of the metal organic framework ZIF-8 for therapeutical applica- brane-coated nanoparticles: a multifunctional biomimetic platform for tions. Appl Mater Today. 2018;11:13–21. cancer diagnosis and therapy. Acta Biomater. 2020;112:1–13. 81. Huang J, Shen H, Wu J, Hu X, Zhu Z, Lv X, Liu Y, Wang Y. Spine Explorer: a 102. Liang X, Ye X, Wang C, Xing C, Miao Q, Xie Z, Chen X, Zhang X, deep learning based fully automated program for efficient and reliable Zhang H, Mei L. Photothermal cancer immunotherapy by erythro- quantifications of the vertebrae and discs on sagittal lumbar spine MR cyte membrane-coated black phosphorus formulation. J Contr Rel. images. Spine J. 2020;20:590–9. 2019;296:150–61. 82. Carnovale C, Bryant G, Shukla R, Bansal V. Identifying trends in gold 103. Dehaini D, Wei X, Fang RH, Masson S, Angsantikul P, Luk BT, Zhang nanoparticle toxicity and uptake: size, shape, capping ligand, and Y, Ying M, Jiang Y, Kroll AV. Erythrocyte–platelet hybrid membrane biological corona. ACS Omega. 2019;4:242–56. coating for enhanced nanoparticle functionalization. Adv Mater. 83. Fang RH, Kroll AV, Gao W, Zhang L. Cell membrane coating nanotech- 2017;29:1606209. nology. Adv Mater. 2018;30:1706759. 104. St John AE, Newton JC, Martin EJ, Mohammed BM, Contaifer D Jr, 84. Zhang X, He S, Ding B, Qu C, Zhang Q, Chen H, Sun Y, Fang H, Long Y, Saunders JL, Brophy GM, Spiess BD, Ward KR, Brophy DF. Platelets retain Zhang R. Cancer cell membrane-coated rare earth doped nanoparticles inducible alpha granule secretion by P-selectin expression but exhibit for tumor surgery navigation in NIR-II imaging window. Chem Eng J. mechanical dysfunction during trauma-induced coagulopathy. J 2020;385:123959. Thromb Haemost. 2019;17:771–81. 85. Ma W, Zhu D, Li J, Chen X, Xie W, Jiang X, Wu L, Wang G, Xiao Y, Liu Z. 105. Sun D, Chen J, Wang Y, Ji H, Peng R, Jin L, Wu W. Advances in refunction- Coating biomimetic nanoparticles with chimeric antigen receptor T alization of erythrocyte-based nanomedicine for enhancing cancer- cell-membrane provides high specificity for hepatocellular carcinoma targeted drug delivery. Theranostics. 2019;9:6885. photothermal therapy treatment. Theranostics. 2020;10:1281. 106. Pitchaimani A, Nguyen TDT, Aryal S. Natural killer cell membrane 86. Mishra P, Jain N. Folate conjugated doxorubicin-loaded membrane infused biomimetic liposomes for targeted tumor therapy. Biomaterials. vesicles for improved cancer therapy. Drug Deliv. 2003;10:277–82. 2018;160:124–37. 87. Xuan M, Shao J, Dai L, Li J, He Q. Macrophage cell membrane cam- 107. Minasyan H. Phagocytosis and oxycytosis: two arms of human innate ouflaged Au nanoshells for in vivo prolonged circulation life and immunity. Immunol Res. 2018;66:271–80. enhanced cancer photothermal therapy. ACS Appl Mater Interfaces. 108. Wang H, Sun Y, Zhou X, Chen C, Jiao L, Li W, Gou S, Li Y, Du J, Chen G, 2016;8:9610–8. et al. CD47/SIRPα blocking peptide identification and synergistic effect 88. Michael M, Vermeren S. A neutrophil-centric view of chemotaxis. Essays with irradiation for cancer immunotherapy. J Immunother Cancer. Biochem. 2019;63:607–18. 2020;8:e000905. 89. Sekeres J, Zarsky V. 180 years of the cell: from Matthias Jakob Schleiden 109. Cao Z, Cheng S, Wang X, Pang Y, Liu J. Camouflaging bacteria by wrap - to the cell biology of the twenty-first century. In: Concepts in cell ping with cell membranes. Nat Commun. 2019;10:1–10. biology-history and evolution. Berlin: Springer; 2018. p. 7–37. 110. Liu J-M, Zhang D-D, Fang G-Z, Wang S. Erythrocyte membrane 90. Goñi FM. The basic structure and dynamics of cell membranes: An bioinspired near-infrared persistent luminescence nanocarriers for update of the Singer-Nicolson model. Biochim Biophys Acta (BBA) in vivo long-circulating bioimaging and drug delivery. Biomaterials. Biomembr. 2014;1838:1467–76. 2018;165:39–47. 91. Shi Y, Xie F, Rao P, Qian H, Chen R, Chen H, Li D, Mu D, Zhang L, Lv P. 111. Ren X, Zheng R, Fang X, Wang X, Zhang X, Yang W, Sha X. Red blood cell TRAIL-expressing cell membrane nanovesicles as an anti-inflammatory membrane camouflaged magnetic nanoclusters for imaging-guided platform for rheumatoid arthritis therapy. J Contr Rel. 2020;320:304–13. photothermal therapy. Biomaterials. 2016;92:13–24. 92. Han Y, Pan H, Li W, Chen Z, Ma A, Yin T, Liang R, Chen F, Ma Y, Jin Y. T cell 112. Rao L, Meng Q-F, Bu L-L, Cai B, Huang Q, Sun Z-J, Zhang W-F, Li A, Guo membrane mimicking nanoparticles with bioorthogonal targeting S-S, Liu W. Erythrocyte membrane-coated upconversion nanoparticles and immune recognition for enhanced photothermal therapy. Adv Sci. with minimal protein adsorption for enhanced tumor imaging. ACS 2019;6:1900251. Appl Mater Interfaces. 2017;9:2159–68. 93. Lv P, Liu X, Chen X, Liu C, Zhang Y, Chu C, Wang J, Wang X, Chen X, Liu 113. Su J, Sun H, Meng Q, Yin Q, Tang S, Zhang P, Chen Y, Zhang Z, Yu H, Li Y. G. Genetically engineered cell membrane nanovesicles for oncolytic Long circulation red-blood-cell-mimetic nanoparticles with peptide- adenovirus delivery: a versatile platform for cancer virotherapy. Nano enhanced tumor penetration for simultaneously inhibiting growth and Lett. 2019;19:2993–3001. lung metastasis of breast cancer. Adv Func Mater. 2016;26:1243–52. 94. Zhang X, Angsantikul P, Ying M, Zhuang J, Zhang Q, Wei X, Jiang 114. Fu S, Liang M, Wang Y, Cui L, Gao C, Chu X, Liu Q, Feng Y, Gong W, Yang Y, Zhang Y, Dehaini D, Chen M. Remote loading of small-molecule M. Dual-modified novel biomimetic nanocarriers improve targeting Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 20 of 21 and therapeutic efficacy in glioma. ACS Appl Mater Interfaces. gradient production and T-cell tumor infiltration. Nat Commun. 2018;11:1841–54. 2017;8:1–15. 115. Chai Z, Hu X, Wei X, Zhan C, Lu L, Jiang K, Su B, Ruan H, Ran D, Fang RH. 137. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. A facile approach to functionalizing cell membrane-coated nanoparti- Cell. 2011;144:646–74. cles with neurotoxin-derived peptide for brain-targeted drug delivery. J 138. Zhang J, Miao Y, Ni W, Xiao H, Zhang J. Cancer cell membrane coated Contr Rel. 2017;264:102–11. silica nanoparticles loaded with ICG for tumour specific photo - 116. Jiang Q, Luo Z, Men Y, Yang P, Peng H, Guo R, Tian Y, Pang Z, Yang W. thermal therapy of osteosarcoma. Artif Cells Nanomed Biotechnol. Red blood cell membrane-camouflaged melanin nanoparticles for 2019;47:2298–305. enhanced photothermal therapy. Biomaterials. 2017;143:29–45. 139. Rao L, Yu GT, Meng QF, Bu LL, Tian R, Lin LS, Deng H, Yang W, Zan M, 117. Chen W, Zeng K, Liu H, Ouyang J, Wang L, Liu Y, Wang H, Deng L, Liu YN. Ding J. Cancer cell membrane-coated nanoparticles for personal- Cell membrane camouflaged hollow prussian blue nanoparticles for ized therapy in patient-derived xenograft models. Adv Func Mater. synergistic photothermal-/chemotherapy of cancer. Adv Func Mater. 2019;29:1905671. 2017;27:1605795. 140. Jin J, Krishnamachary B, Barnett JD, Chatterjee S, Chang D, Mironchik 118. Li B, Wang F, Gui L, He Q, Yao Y, Chen H. The potential of biomimetic Y, Wildes F, Jaffee EM, Nimmagadda S, Bhujwalla ZM. Human cancer nanoparticles for tumor-targeted drug delivery. Nanomedicine. cell membrane-coated biomimetic nanoparticles reduce fibroblast- 2018;13:2099–118. mediated invasion and metastasis and induce T-cells. ACS Appl Mater 119. Rosales C. Neutrophil: a cell with many roles in inflammation or several Interfaces. 2019;11:7850–61. cell types? Front Physiol. 2018;9:113. 141. Wang C, Wu B, Wu Y, Song X, Zhang S, Liu Z. Camouflaging nanopar - 120. Morikis VA, Simon SI. Neutrophil mechanosignaling promotes integrin ticles with brain metastatic tumor cell membranes: a new strategy to engagement with endothelial cells and motility within inflamed ves- traverse blood–brain barrier for imaging and therapy of brain tumors. sels. Front Immunol. 2018;9:2774. Adv Func Mater. 2020;30:1909369. 121. He Z, Zhang Y, Feng N. Cell membrane-coated nanosized active tar- 142. Kumar P, Van Treuren T, Ranjan AP, Chaudhary P, Vishwanatha JK. In vivo geted drug delivery systems homing to tumor cells: a review. Mater Sci imaging and biodistribution of near infrared dye loaded brain-meta- Eng C. 2020;106:110298. static-breast-cancer-cell-membrane coated polymeric nanoparticles. 122. Xue J, Zhao Z, Zhang L, Xue L, Shen S, Wen Y, Wei Z, Wang L, Kong L, Nanotechnology. 2019;30:265101. Sun H. Neutrophil-mediated anticancer drug delivery for suppres- 143. Ribas A. Adaptive immune resistance: how cancer protects from sion of postoperative malignant glioma recurrence. Nat Nanotechnol. immune attack. Cancer Discov. 2015;5:915–9. 2017;12:692–700. 144. Zhang L, Li R, Chen H, Wei J, Qian H, Su S, Shao J, Wang L, Qian X, Liu B. 123. Cao X, Hu Y, Luo S, Wang Y, Gong T, Sun X, Fu Y, Zhang Z. Neutrophil- Human cytotoxic T-lymphocyte membrane-camouflaged nanoparticles mimicking therapeutic nanoparticles for targeted chemotherapy of combined with low-dose irradiation: a new approach to enhance drug pancreatic carcinoma. Acta Pharmaceut Sin B. 2019;9:575–89. targeting in gastric cancer. Int J Nanomed. 2017;12:2129. 124. Combes F, Meyer E, Sanders NN. Immune cells as tumor drug delivery 145. Um W, Ko H, You DG, Lim S, Kwak G, Shim MK, Yang S, Lee J, Song Y, Kim vehicles. J Control Rel. 2020;327:70–87. K, Park JH. Necroptosis-inducible polymeric nanobubbles for enhanced 125. Wu M, Le W, Mei T, Wang Y, Chen B, Liu Z, Xue C. Cell membrane cancer sonoimmunotherapy. Adv Mater. 2020;32:1907953. camouflaged nanoparticles: a new biomimetic platform for cancer 146. Chen DS, Mellman I. Oncology meets immunology: the cancer-immu- photothermal therapy. Int J Nanomed. 2019;14:4431. nity cycle. Immunity. 2013;39:1–10. 126. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, 147. Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, Steven NM, Esmaeili SA, Mardani F, Seifi B, Mohammadi A, Afshari JT, Sahebkar A. Kerr DJ, Young LS, Adams DH. A phase II study of adoptive immuno- Macrophage plasticity, polarization, and function in health and disease. therapy using dendritic cells pulsed with tumor lysate in patients with J Cell Physiol. 2018;233:6425–40. hepatocellular carcinoma. Hepatology. 2009;49:124–32. 127. Najafi M, Hashemi Goradel N, Farhood B, Salehi E, Nashtaei MS, 148. Zhang B, Yin Y, Lai RC, Lim SK. Immunotherapeutic potential of extracel- Khanlarkhani N, Khezri Z, Majidpoor J, Abouzaripour M, Habibi M. Mac- lular vesicles. Front Immunol. 2014;5:518. rophage polarity in cancer: a review. J Cell Biochem. 2019;120:2756–65. 149. Mbongue JC, Nieves HA, Torrez TW, Langridge WH. The role of dendritic 128. Hu C, Lei T, Wang Y, Cao J, Yang X, Qin L, Liu R, Zhou Y, Tong F, Ume- cell maturation in the induction of insulin-dependent diabetes mellitus. shappa CS. Phagocyte-membrane-coated and laser-responsive nano- Front Immunol. 2017;8:327. particles control primary and metastatic cancer by inducing anti-tumor 150. Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immu- immunity. Biomaterials. 2020;255:120159. nol. 2016;37:855–65. 129. Gay LJ, Felding-Habermann B. Contribution of platelets to tumour 151. Cheng S, Xu C, Jin Y, Li Y, Zhong C, Ma J, Yang J, Zhang N, Li Y, Wang C. metastasis. Nat Rev Cancer. 2011;11:123–34. Artificial mini dendritic cells boost T cell-based immunotherapy for 130. De Witt SM, Swieringa F, Cavill R, Lamers MM, Van Kruchten R, Masten- ovarian cancer. Adv Sci. 2020;7:1903301. broek T, Baaten C, Coort S, Pugh N, Schulz A. Identification of platelet 152. Zhang C, Zhang J, Shi G, Song H, Shi S, Zhang X, Huang P, Wang Z, function defects by multi-parameter assessment of thrombus forma- Wang W, Wang C. A light responsive nanoparticle-based delivery tion. Nat Commun. 2014;5:1–13. system using pheophorbide a graft polyethylenimine for dendritic cell- 131. Nelson VS, Jolink A-TC, Amini SN, Zwaginga JJ, Netelenbos T, Semple based cancer immunotherapy. Mol Pharm. 2017;14:1760–70. JW, Porcelijn L, de Haas M, Schipperus MR, Kapur R. Platelets in ITP: 153. Fang RH, Jiang Y, Fang JC, Zhang L. Cell membrane-derived nanomate- victims in charge of their own fate? Cells. 2021;10:3235. rials for biomedical applications. Biomaterials. 2017;128:69–83. 132. Chen S, Lv M, Fang S, Ye W, Gao Y, Xu Y. Poly (I: C) enhanced anti-cervical 154. Sun Q, Wu J, Jin L, Hong L, Wang F, Mao Z, Wu M. Cancer cell cancer immunities induced by dendritic cells-derived exosomes. Int J membrane-coated gold nanorods for photothermal therapy and radio- Biol Macromol. 2018;113:1182–7. therapy on oral squamous cancer. J Mater Chem B. 2020;8:7253–63. 133. Shang Y, Wang Q, Wu B, Zhao Q, Li J, Huang X, Chen W, Gui R. Platelet- 155. Rao L, Bu LL, Meng QF, Cai B, Deng WW, Li A, Li K, Guo SS, Zhang WF, membrane-camouflaged black phosphorus quantum dots enhance Liu W. Antitumor platelet-mimicking magnetic nanoparticles. Adv Func anticancer effect mediated by apoptosis and autophagy. ACS Appl Mater. 2017;27:1604774. Mater Interfaces. 2019;11:28254–66. 156. Wu H-H, Zhou Y, Tabata Y, Gao J-Q. Mesenchymal stem cell-based 134. Wu H, Mu X, Liu L, Wu H, Hu X, Chen L, Liu J, Mu Y, Yuan F, Liu W. Bone drug delivery strategy: from cells to biomimetic. J Contr Rel. marrow mesenchymal stem cells-derived exosomal microRNA-193a 2019;294:102–13. reduces cisplatin resistance of non-small cell lung cancer cells via 157. He H, Guo C, Wang J, Korzun WJ, Wang X-Y, Ghosh S, Yang H. Leutu- targeting LRRC1. Cell Death Dis. 2020;11:1–14. some: a biomimetic nanoplatform integrating plasma membrane 135. Nath S, Mukherjee P. MUC1: a multifaceted oncoprotein with a key role components of leukocytes and tumor cells for remarkably enhanced in cancer progression. Trends Mol Med. 2014;20:332–42. solid tumor homing. Nano Lett. 2018;18:6164–74. 136. Gordon-Alonso M, Hirsch T, Wildmann C, van der Bruggen P. Galectin-3 158. Sun M, Duan Y, Ma Y, Zhang Q. Cancer cell-erythrocyte hybrid captures interferon-gamma in the tumor matrix reducing chemokine membrane coated gold nanocages for near infrared light-activated L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 21 of 21 photothermal/radio/chemotherapy of breast cancer. Int J Nanomed. 2020;15:6749. 159. Gong C, Yu X, You B, Wu Y, Wang R, Han L, Wang Y, Gao S, Yuan Y. Macrophage-cancer hybrid membrane-coated nanoparticles for targeting lung metastasis in breast cancer therapy. J Nanobiotechnol. 2020;18:1–17. 160. Li M, Xu Z, Zhang L, Cui M, Zhu M, Guo Y, Sun R, Han J, Song E, He Y, Su Y. Targeted noninvasive treatment of choroidal neovascularization by hybrid cell-membrane-cloaked biomimetic nanoparticles. ACS Nano. 2021;15:9808–19. 161. Giampietro C, Taddei A, Corada M, Sarra-Ferraris GM, Alcalay M, Caval- laro U, Orsenigo F, Lampugnani MG, Dejana E. Overlapping and diver- gent signaling pathways of N-cadherin and VE-cadherin in endothelial cells. Blood J Am Soc Hematol. 2012;119:2159–70. 162. Pisano S, Pierini I, Gu J, Gazze A, Francis LW, Gonzalez D, Conlan RS, Corradetti B. Immune (Cell) derived exosome mimetics (IDEM) as a treatment for ovarian cancer. Front Cell Dev Biol. 2020;8:553576. 163. Susa F, Limongi T, Dumontel B, Vighetto V, Cauda V. Engineered extracellular vesicles as a reliable tool in cancer nanomedicine. Cancers. 1979;2019:11. 164. Jin K, Luo Z, Zhang B, Pang Z. Biomimetic nanoparticles for inflamma- tion targeting. Acta Pharmaceut Sin B. 2018;8:23–33. 165. Xia Y, Rao L, Yao H, Wang Z, Ning P, Chen X. Engineering mac- rophages for cancer immunotherapy and drug delivery. Adv Mater. 2020;32:2002054. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Nanobiotechnology Springer Journals

Nanocarriers surface engineered with cell membranes for cancer targeted chemotherapy

Loading next page...
 
/lp/springer-journals/nanocarriers-surface-engineered-with-cell-membranes-for-cancer-0RGwsaU9P0

References (178)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2022
eISSN
1477-3155
DOI
10.1186/s12951-022-01251-w
Publisher site
See Article on Publisher Site

Abstract

Background delivered through nanoparticles has not yet achieved Cancer has been a worldwide concern for a long period its full therapeutic potential. of time and is the second largest cause of mortality [1]. The drug-delivery system’s (DDSs) technology contin - Conventional chemotherapy, as one of the most fre- ues to advance, making it possible to administer more quently used methods for cancer treatment, remains potent drugs [9]. Drug research efforts are significantly unsatisfactory owing to the significant side effects and aided by therapeutic compounds’ capacity to remain the poor targeting ability of anti-cancer drugs [2]. To intact in a hostile extracellular milieu [10]. In this con- overcome these issues, significant research and devel - nection, efforts to reduce immunogenicity and improve opment has been conducted on targeted drug delivery biopharmaceutical stability through modification of systems (TDDS), particularly nanocarrier-based TDDS biopharmaceuticals have increased [11]. Cells in the early [3]. The benefits of nanocarriers, which include the 1980s were used as drug delivery vehicles, which substan- ability to be modified, a large capacity for drug load - tially increased the drugs’ retention and targeting capa- ing, and tunable physiochemical characteristics, make bilities [12]. Despite the increasing use of live cell-based them ideal for encapsulating anti-cancer drugs and carriers, several shortcomings persist. One major con- altering their stability, solubility, and in  vivo behaviour cern is passenger drug activity, as drugs may be digested [4]. Nevertheless, surface modification of nanocarriers by the cell carrier’s lysosomes [13]. Moreover, drug may enhance their blood circulation and enable more release is difficult to control due to exocytosis or leak - precise targeting, thus increasing effectiveness while age during transport [14]. Faced with these challenges, trying to minimize side effects [5 ]. However, there are scientists recently discovered a natural way to design also many disadvantages that make it difficult for nano - biomimetic cell membrane nanocarriers. At first, the bio - carriers to live up to clinical standards. The immune mimetic cell membrane nanocarriers were made from a system recognizes and eliminates the majority of nano- poly (lactic-co-glycolic acid) (PLGA) core and a red blood carriers as foreign substances. Since the polyethylene cell (RBC) membrane shell, using a co-extrusion process glycol (PEG), a hydrophilic polymer, was initially incor- [15]. Then, different cell membrane-coated nanocarriers porated into a protein medication [6], PEGylation has (CMCNs) were explored with different nanocarrier cores been the most frequently utilized modification tech - and membrane materials. The incorporation of nanocar - nique in drug delivery applications [7]. Additionally, riers into the cell membrane merges the advantages of the targeted capacity of nanocarriers was highly reli- material science and biomimicry. It is important to note ant on the surface modification, which was challenging that CMCNs can be portrayed as autogenous cells to pro- to manufacture and accomplish [8]. As a result, TDDS long blood circulation time and avoid immune system L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 3 of 21 elimination, both of which are required for the enhanced to the whole cell. Because a longer circulation time ben- permeability and retention (EPR) effect of cancer tar - efits with the potential of sustained drug delivery and geted chemotherapy [16] (Fig. 1). increases the probability of sustained distribution into Moreover, different cell membranes may confer dif - the circulation [20]. The biomimetic CMCNs provide ferent functions on CMCNs, resulting in varying in vivo bio-modulation and more control in this regard. The behaviour. Biomimetic technology, a relatively new pro- CMCNs prepared by coating RBC membrane on PLGA cedure, satisfies these requirements and is currently nanocarriers improved the nanocarriers’ retention in being used in designing drug nanocarriers [17, 18]. By the blood by 72 hours, compared to 15.8 hours for typi- drawing inspiration from nature that comprises biologi- cal synthetic stealth nanocarriers [15]. Moreover, PLGA cal elements and living matter, this technology aims to nanocarriers with a fluorocarbon core masked in an overcome the shortcomings of current drug delivery sys- RBC membrane were used for delivering oxygen to solid tems. An ideal biomimetic delivery system exploits path- tumours, demonstrating another application of CMCNs ogens’ immune evasion and intracellular uptake tactics. delivery to improve blood circulation time via the EPR However, delivery systems derived from pathogens con- approach [21]. tinue to raise safety concerns, including immunogenicity The reduced immunogenic characteristics of cancer and virulence [19]. cell membranes and their homing abilities improve tar- geted drug delivery at the cancer site. In this respect, Cao Advantages of CMCNs based drug delivery systems et  al. investigated the interaction between VCAM-1 of CMCNs have notably contributed to suppressing drug metastatic cancer cells with macrophage α4 proteins to resistance in the use of nanocarriers for cancer thera- transport cytotoxic anticancer drugs to the lungs [22]. pies. Biomimetic CMCNs possess special characteristics, Using the adhesion characteristics of galectin-3 and T such as prolonged drug delivery, immunological eva- antigen in cancer cell membranes, Fang et  al. demon- sion, homotypic targeting, longer blood circulation, and strated homotypic tumour targeting [23]. Furthermore, specific ligand/receptor recognition. To get beyond the when compared to other active targeting methods, incor- restrictions of cell toxicity, differentiation, and sensitivity porating iron oxide nanocarriers into fractured cancer in cell-based delivery systems, CMCNs utilize therapeu- cell membranes for tumor targeting demonstrated supe- tically relevant cell membrane proteins as an alternative rior homing to homologous tumors in vivo [24]. Recently Fig. 1 Nanocarriers with a cell membrane coating for cancer drug delivery. Different types of cell membranes are used to encapsulate various types of nanocarrier core for cancer treatment Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 4 of 21 designed leuko-like vectors (LLV) targeting metastatic therapy [33]. For example, the membrane of RBCs is niches utilizing neutrophil membrane-coated nanocarri- rich with glycophorins that play a key role in attracting ers have shown a two- to threefold increase in metastatic pathogens to their surface and killing them via oxytosis foci accumulation compared to PLGA-PEG nanocarri- [32]. The application of an RBC membrane to the nano - ers and bare nanocarriers, respectively [25]. This affin - carriers thereby increases pathogen clearance, long- ity for metastatic niches is enhanced by the presence of term circulation, and cell viability. Platelets interact with N cadherin, Mac-1, and other sticky proteins produced injured endothelial cells and engage with immune cells on neutrophil membranes on CMCNs, as opposed to to mobilize them toward the inflamed site [34]. As a the usual PEG coating employed to prolong circulation result, covering the nanocarriers with the platelet mem- half-life and prevent clearance [26]. Interestingly, PLGA branes allows for selective adherence to tumour tissues nanocarriers coated with T lymphocyte membranes were or wounded vessels, targeting circulatory tumour cells, also capable of retaining their lymphocyte coating and pathogen eradication, and the capability to elude detec- evading lysosome sequestration, while bare nanocarri- tion by macrophages. Similarly, macrophage membranes ers were caught in endolysosomal compartments prone like other leukocytes carry adhesion molecules like to breakdown in in  vivo [27]. Moreover, this study also VLA-4, LFA-1, PSGL-1, L-selectin, and P-selectin that discovered that T lymphocyte-coated nanocarriers had a help with cell adherence [35]. u Th s, coating the nanocar - twofold increase in particle density throughout tumours rier with macrophage membrane has the ability to bind in mice when compared to naked nanocarriers. Numer- pathogens while avoiding macrophage recognition and ous additional research groups are attempting to harness offering active targeting at the cancer site. Moreover, the cell membrane’s inherent properties to create biomi- tumor-specific adhesion molecules and antigens such as metic drug carriers for cancer treatments. mucoprotein-1, epithelial-adhesion molecules, lympho- cyte-homing receptors (like CD44), galectin-3, integrins, Considerations of CMCNs and cadherins are overexpressed on the surface of cancer Choice of cell membrane cell membranes [36]. These antigens and adhesion mol - A thorough understanding of the homeostasis, func- ecules play a critical role in the contacts among cells and tion, and structure of cells in their complex physiologi- between cells and the surrounding tissue matrix. Gener- cal context provides key hints for better biointerfacing ally, cancer cell membranes can cling to their homolo- of synthetic DDSs [28]. A delivery system with the abil- gous cells [37]. So, wrapping a nanocarrier with a cancer ity to protect cargo and carry cell features like autono- cell membrane prevents macrophage detection, allowing mous activity, compartmentalization, flexibility, and for homotypic tumour targeting, and contributes to the form can be more convenient and beneficial than other design of personalized cancer therapy. delivery systems. The cell membrane repeats the surface functionality of cells and extracellular vesicles as it is the Cell source fundamental structural component of them. It is primar- In order to use maximum cell membrane properties, ily made up of carbohydrates, proteins, and lipids, and it is essential to consider the state, form, and source of it interacts with the environment to survive and grow the cell. In this connection, Evangelopoulos et  al. dem- [29]. Carbohydrates play a part in cellular recognition, onstrated that the cell source determines the immuno- whereas proteins are responsible for adhesion and sign- genicity of biomimetic nanocarriers [38]. They studied aling, and lipid bilayer formation combines structural multilayer cell membrane generated vesicles from various fluidity and stiffness [30–32]. Cell membranes can be dif - sources for phagocytosis, opsonization, and targeting of ferentiated based on the properties and composition of inflamed regions. Literature showed that the use of a syn - these three components in them. The potential to profit geneic cell membrane coating increased the avoidance from native cell membrane functions has sparked tre- of absorption by the liver and immunological repertoire mendous scientific interest in coating nanocarriers. If cells [38]. To isolate the cell membrane for the coating done appropriately, the cell membrane retains its capabil- of nanocarriers, it is preferred to choose homotypic cells ity, and its coating enhances biointerfacing. in a healthy state and nourishing phase. The real thera - The selection of the appropriate cell type or cell mem - peutic effectiveness of CMCNs requires homogeneity of brane is crucial for ensuring site-specific distribution the cell population. To fulfil this requirement, quanti - and targeting as well as for minimizing adverse interac- fication or expression levels of specific surface markers tions with complementing systems in vivo. Every cell type (e.g., receptors or ligands) plays a dominant role. For this has unique biological features, making them suitable for purpose, flow cytometry, Blot Western, and SDS-PAGE certain therapeutic applications such as infectious dis- techniques can be used to evaluate the cellular state and eases, inflammatory diseases, cancer, and personalized homogeneity of cell membranes [39]. Identification of L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 5 of 21 cell biomarkers and other ligands for signal transduction, of mesenchymal stem cells, which vary across individu- targeting, or any other approach would enhance transla- als, cell groups, and even batches. The expansion of mes - tional effects. enchymal stem cells in in  vitro not only alters mRNA expression patterns but also affects the surface proteins Membrane stability involved in migration and adhesion (e.g., C-met/HGF, CMCNs are preferred for use over targeting nanocar- CXCR7, CXCR4, etc.) [44]. In the case of nanocarriers riers prepared via a bottom-up approach because they coated with immune cell membrane, it is essential to con- possess numerous characteristics, including signal trans- sider the state and cellular source of immune cells, since duction, immune evasion, targeting, and therapeutic they undergo different modifications throughout the advantages. To maximize the therapeutic potential of pro- and post-inflammatory phases (e.g., pro- and post- CMCNs, the structural and functional characteristics of inflammatory macrophages M1 and M2). the cell membrane should be preserved prior to coating While obtaining the desired membranes is still an drug carriers. The cell membrane’s stability is critical in attractive approach, it is becoming increasingly favora- determining the overall durability of CMCNs. The micro - ble to modify the cell surface using proteins, peptides, or environment of tissue and circulation naturally creates small molecules before harvesting the membranes [45]. torque and shear forces on cells and nanocarriers. Cells In this scenario, cell membrane receptors are becoming survive with these forces and respond to them by actively less sensitive, and this is unknown at this time. In the case modulating their cytoskeleton-membrane interactions, of highly biotinylated membranes of erythrocytes, they lipid profile, ligand density, and ligand concentration. For are more likely to be taken up by macrophages because of example, the interaction of intracellular proteins with the the presence of C3b proteins on them. It is suggested that cell membrane strengthens the reliability of natural cells. biotinylation may also disable complement regulators or During the isolation of the membrane, some key stability self-markers on the cell surface [46]. As CMCNs appear regulators of the cell membrane may be lost or changed. to have no significant effect on cellular behaviours, they As a result, determining the overall membrane stability do not entirely reflect what the cells naturally do. Stephan of CMCNs becomes critical before moving further with et al. performed a detailed investigation of nanocarriers- biomimetic-based treatment [40]. Numerous techniques tethered T cells to monitor synapse formation, transmi- for determining the stability of membrane structures are gration, antigen, and cell division. They found that the described in the literature. For visualizing the structural ability of the cell to perform physiological functions was integrity and morphology of cell membranes, advanced not affected by the conjugation of nanocarriers to the cell fluorescence, lipophilic dye enhanced, Cryo-TEM, and membrane [40]. The degree of immune response vari - spectrophotometric techniques, for example, are all ability is proportional to the variety of different sources extremely useful [41]. When it comes to the mechanical employed in cell membrane engineering and to the tech- or elastic integrity of membranes, ektacytometry may nology used to design the membranes. To successfully be the best tool for determining membrane elongation apply biomimetic-based drug delivery applications to the in dynamic shear stress [42]. Additionally, the source of clinic, it is essential to have extensive CMCNPs charac- lipid composition in the cell also influences the overall terization and qualification. stability of CMCNs. In one study comparing the lipid- omic profiles of cells, a higher proportion of unsaturated Cell membrane extraction phospholipids was observed in primary cell cultures than In order to successfully isolate the cell membrane, cell other cultured. X-ray scattering, FTIR, and colorimetric membrane extraction protocols must ensure that there lipid assays are all useful tools for assessing the qualita- is minimal or no cytosol, mitochondrial, or nuclear tive composition of phospholipids [43]. contamination. Making use of a pure cell membrane improves surface coating efficiency and uniformity, Membrane‑related proteins allowing for maximum functional and structural replica- The CMCNs interact with the local environment of tis - tion on the nanocarrier surface. To preserve membrane sues and cells through proteins present on the cell mem- proteins from degeneration, the extraction medium is branes. So, the appropriate membrane proteins must supplemented with phosphatase/protease inhibitor cock- be kept up in the cell culture. Several transfection and tails that are stored at ice-cold temperatures. Prior to chemical signaling methods may be used to regulate extraction, cells are thoroughly cleaned with saline buffer protein expression and cellular states in culture. In fact, to remove any remaining remnants of the cell culture long-term cell growth of some cell types may alter their medium. desirable characteristics for CMCNs applications. For Some cells lack nuclei (e.g., RBCs and platelets), mak- example, the culture condition affects the phenotypes ing membrane extraction easy. During membrane Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 6 of 21 extraction, cells are separated first from their tissues classified as organic and inorganic, where liposomes, using the most suitable techniques. For RBCs, a hypo- gelatin, and PLGA are organic templates, while inorganic tonic treatment certainly disintegrates the cells and frees templates include iron oxide (F e O ), gold, mesoporous 3 4 the cell membrane to collect through centrifugation in silica, upconversion nanoparticles (UCNPs), PLNPs, and the form of a pink RBC pallet [47]. Again and again, cen- MOFs. Organic templates are simple to use and provide trifugation purifies the pallet from haemoglobin impu - benefits, including biocompatibility, biodegradability, and rities. For platelets, it is recommended to do multiple nontoxicity [53]. Inorganic templates, on the other hand, freeze–thaw sequences to rapture their membrane by have electrical, optical, and magnetic properties that breaking ice crystals to release the cytosol [48]. The free influence their selection in a CMCN [54]. cell membrane is then collected through centrifugation. For clinical translation, template biodegradability and Sometimes, the collected platelet membranes are treated biocompatibility are critical which are influenced by the with a discontinuous sucrose gradient to purify the plate- degradation and byproducts formation and their sub- let membrane from any high-density granules, proteins, sequent interactions with human body. 231,231 Renal and intact platelets. clearance helps avoid the templates adverse effects [55]. Extraction of the membrane from nucleus-containing FDA-approved templates are regarded the safest in terms cells is slightly more difficult than from nucleus-free cells. of toxicities. Because most organic templates are safer Nucleus-containing cells include β-cells, fibroblasts, can - than inorganic ones, they have been practiced in clini- cer stem cells, and immune cells (e.g., T cells, NK cells, cal trials [56]. In 2011, a PLGA nanoparticle was used neutrophils, monocytes/macrophages). These cells can as a template to build these imitating systems [15]. As be isolated from established cell lines like MCF-7, 4T1, a synthetic polymer, PLGA can be fabricated into nano J447, NK-92, etc., or from blood or tissues (stem cells, and microparticles and have been commonly used for cancer cells, T cells, neutrophils, NK cells, etc.). By com- RBC, platelets, cancer cells, neutrophils, dendritic cells, bining hypotonic treatment with physical disruption pro- macrophages, cardiac stem cells, and various other tem- cedures, it produces an extract that contains high-density plates [47, 49, 57–60]. Gelatin, a natural polypeptide granules, intact cells, and free cell membranes. Finally, widely used in medicines, food, and cosmetics, has also the cell membrane is isolated from the mixture through been utilized for assembly of CMCNs. Patient-derived the use of discontinuous sucrose gradient ultrafiltration tumour cells, T-cell, stem cell, and RBC are employed to or differential centrifugation [49, 50]. coat gelatin templates for CMCNs [61–64]. Liposomes Membrane functional components such as cholesterol have also been used as core for cancer cells, RBCs, and (making structural components), carbohydrates (cellular macrophages membranes [22, 65, 66]. Perfluorocarbons recognition components), and transmembrane proteins (PFCs) are also among the regulated templates where (adhesion and signaling components) can be lost dur- PFCs (Fuosol-DA) was approved in 1989 but was with- ing membrane isolation. Cholesterol helps keep the cell drawn from market shortly due to storage issues [67]. membrane rigid. This loss may reduce the membrane’s However, PFCs are biocompatible, biodegradable, and mechanical stability. Moreover, proteins also act as mem- have high oxygen-carrying capacity with ~ 20 times brane skeleton stabilizers by selectively attaching to the greater than water thus can be used for oxygen delivery junction complex as well as other membrane proteins to smallest capillaries and hypoxic tumour locations [68]. such as tropomyosin [51]. Therefore, hypotonic buffers The toxicity of inorganic templates depends on the type containing divalent ions (such as MgCl ) or even add- of utilized metal and its breakdown in  vivo. Silica is the ing cholesterol can be effective in reducing protein loss safest (FDA-approved) inorganic template and is biode- while maintaining membrane stability [52]. Moreover, gradable and biocompatible [69]. It has been a research the right pH, soft rapturing procedures, proper ice-cold focus for templates due to certain properties including conditions, and mild lysis buffer must be adopted for high surface area, porosity, and drugs or photosensitiz- membrane extraction to avoid denaturation of trans- ers loading capability [70]. CMCNs have been reported membrane proteins/receptors. Once the cell membrane using spherical silica nanoparticles on RBC, cancer cells, has been isolated, it is freeze dried and kept at −  80  °C and macrophage membranes [71, 72]. Mesoporous silica to ensure that membrane proteins retain their long-term nanoparticles can be tuned and chemically modified into consistency and features. various shapes and sizes for desired applications, e.g., prolonged antibacterial property and regulating endoge- Choice of template nous reactive oxygen species for oxidative treatment [73]. A template is a structural component of the CMCNs When combined with CMC mimics, these tunable fea- which can be used for diagnosis and drug delivery tures could offer therapeutic benefits. The surface charge due to its various desirable features. Templates can be of silica templates can be changed with 3- aminopropyl L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 7 of 21 triethoxysilane for CTC detection [74, 75]. Iron ions are to lysate them. Second, the purification of the mixture harmless biodegradation products of Fe O nanoparti- to separate cellular components and cell membranes by 3 4 cles. MSCs and HeLa cells were employed as membranes centrifugation [83]. The centrifugation process will be in several CMC mimics employing Fe O templates [76– different depending on the cell type. For example, irregu - 3 4 78]. MOFs are 3D structures generated by the complexa- lar sucrose gradient centrifugation is needed to prepare tion of organic ligands and metal ions [79]. Their toxicity eukaryote cell membranes because this treatment sepa- is associated with the type of organic linkers and met- rates the membrane from nuclei and other cell compo- als employed. For example, zinc-based MOFs [zeolitic nents. Whereas nuclei-free membranes like RBCs do not 2+ imidazolate (ZIF-8)] degrade to release Zn ions, an require this treatment. Third, preparation of the inner endogenous element with a less detrimental effect on the core. Liposomes, gelatin, PLGA, poly (-caprolactone), human body [80]. Post-degradation of TPP-based Gd/Zn iron oxide nanoparticles, gold nanoparticles, mesoporous 3+ 2+ MOFs releases gadolinium (Gd ) and zinc (Zn ) ions, silica nano-capsules, silicon nanoparticles, and other syn- 3+ where Gd is harmful to the kidneys and can pass the thetic materials make up the inner cores. The inner core blood–brain barrier to accumulate in the brain [81]. Due selection for CMCNs is based on the types of cargo to be to their structural arrangement, MOFs have excellent transported (Fig. 2). porosity, surface area, and photosensitizer loading capa- To prepare CMCNs, the inner core nanoparticles and bility. Gold microparticles are another inorganic tem- the cell membranes are fused together. The fusion pro - plate, but they are not biodegradable and may be harmful cess must be carried out in such a way that it should not thus, nano or ultra-small templates of gold for fast renal result in protein denaturation or drug leakage. The two clearance is ideal [82]. Gold particles can be shaped into most frequently used procedures for the fusion of the nanoparticles, nanoshells, nanorods, and nanocages, inner core into cell membranes are ultrasonic treatment which are all used to fabricate CMCNs. and membrane extrusion [84, 85]. Sonication has been employed to fuse the PLGA core into the platelet mem- Procedures for engineering CMCNs brane, which exhibits various “self-recognized” proteins Preparation of CMCNs [86]. The duration, power, and frequency of the sonica - The preparation of CMCNs can be processed through tion should be adjusted to minimize drug leakage and four major steps. The first step is to separate the mem - protein denaturation and enhance fusion efficiency. In branes from the parent cells by using a hypotonic buffer membrane extrusion, membranes are extruded using a Fig. 2 The preparation of cell membrane-coated nanocarriers is a multistep process. Cell membranes are typically synthesized in three steps: cell lysis, membrane separation, and extrusion to obtain homogenous cell membrane vesicles Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 8 of 21 technique known as sequential extrusion. In this tech- the biosynthesis of certain proteins using the parental nique, samples (a mixture of core nanoparticles and cell protein machinery. membrane) are extruded through different-sized pores. Pre-modification approach results in a more homog - It is crucial to control the nanoparticle-to-cell membrane enous and secure source of membrane, but the types of ratio in order to ensure complete surface coverage for ligand and component possibilities are inadequate as both of these techniques [87]. A new microfluidic elec - compared to the post-modification approach. Several troporation-based procedure has recently been devel- post-modification methods have been developed due to oped to apply a full membrane coating on the inner core, the availability of divers and convenience modified mate - which means that different factors, such as flow veloc - rials. The materials used for modification range from nat - ity, duration, and voltage, must be tailored to meet the ural lipids [94], nucleic acids [95], and proteins [96], to desired results [88]. synthetic components [97]. Cholesterol is one lipid that is used to modify vesicles derived from cell membranes for CMCNs. It plays an important role in the formation Modification of cell membrane of the cell membrane’s lipid bilayer structure. Changes The structure, functions, and components of cell mem - in cholesterol ratios can affect the rigidity and fluidity of branes have become more understandable as cell biology membranes [98]. The addition of cholesterol increases progresses [89]. The composition of the cell membrane is the stability of vesicles derived from cell membranes in mainly composed of a lipid bilayer, while protein and car- terms of their resistance to environmental pH changes bohydrate molecules are lodged in the hydrophobic part [94]. In the case of RBCs, adding cholesterol to RBCs and of the lipid layer [90]. One of the major functions of the slightly heating them for 10 min increased the rigidity of cell membrane is to protect the intracellular organelles, their vesicles, significantly improving the efficacy of drug which transport nutrients, process waste, and regulate loading. Proteins can be conjugated to the cell mem- metabolism. Moreover, cell-to-cell contacting signal- brane through insertion or conjugation. For instance, a ing is also regulated by the cell membrane. Therefore, bifunctional linker functionalized with N-hydroxysuc- the cell membrane can be modified for desirable func - cinimide at one end and maleimide at another terminal tions. The modification of the cell membrane may be was used to conjugate hyaluronidase to the RBC mem- processed either before disrupting the parent cells (i.e., brane [96]. Another study used an amphiphilic lipid pre-modification) or additional components are subse - to anchor protein to the surface of a membrane vesicle quently introduced into membranes after isolation (i.e., [97]. In this approach, streptavidin was first attached post-modification). to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- In pre-modification, the properties of the parent cell N-[maleimide (polyethylene glycol)-2000] and then the membrane are modified at metabolic or genetic levels. lipid tail was inserted into the cell membrane. Inserting a Parent cells are treated with certain chemical or physi- protein-conjugated lipid into the cell membrane enables cal stresses to induce the expression of specific lipid or protein affixing without disturbing membrane surface protein components, or to modify the structure of mem- proteins, thereby increasing the likelihood of membrane brane hydrocarbon chains [91]. Metabolic glycosylation proteins retaining their intact structure. However, chemi- is mainly used to control expression levels of native gly- cal conjugation of lipid moieties with a protein may alter cans, but it can also be used to introduce artificial mono - the configuration of associated proteins. Strategies for saccharides into glycol-conjugates [92]. RBCs are one of conjugating proteins with lipid moieties at specific sites the most frequently used sources for generating vesicles must be carefully designed to minimize possible configu - derived from cell membranes. However, it is impossible rational changes. Another substance used to modify the to modify mature RBCs genetically due to the absence vesicles derived from the cell membrane is nucleic acids. of nuclei in mature RBCs. To overcome this problem, Lv Aptamers are short single-strand oligonucleotides that et al. used the CRISPR gene-editing strategy to engineer may precisely attach to a target substrate. Peng et al. used an RBC membrane expressing the tripeptide Asn-Gly- the 26-mer G-quadruplex oligonucleotide AS1411, which Arg (NGR) [93]. Transgenic mice were generated in this binds to nucleolin, to modify the membrane of cancer study by inserting NRG peptide coding in the pre-embryo cells [95]. The AS1411 aptamer enabled tumor-targeting stage. A genetic analysis of newborn mice was used to of membrane vesicles because of the overexpression of validate the NGR expression. RBCs were isolated from nucleolin in tumor tissue (Fig. 3). these mice and used to generate RBC membrane vesicles It is well known that synthetic polymers, particularly for targeted delivery of an oncolytic virus to tumors. As PEG, have been used to modify cell membrane for the exogenous physical or chemical coupling onto vesicles preparation of CMCNs [99, 100]. By protecting CMCNs may alter protein function, so genetic engineering allows from phagocytosis, PEG conjugation increases their L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 9 of 21 Fig. 3 Post-modification of cell membrane. Cell membranes can be modified with different molecules or biomarkers to modulate their biological behaviors. An illustration of aptamers (A), protein (B), cholesterol (C), and synthetic polymer (D) conjugated cell membrane colloidal stability and thus their circulation half-life example, RBC membrane-coated nanocarriers can avoid in vivo. PEGylation can be accomplished merely through reticuloendothelial clearance because they express CD47 the incubating PEG lipid derivatives and cell membrane (immunoregulatory marker) [103]. Similarly, P-selectin at 37 °C. PEG lipid tails easily insert into membrane lay- is a ligand of the CD44 receptor found in platelet mem- ers in these conditions. One issue with current PEGyla- branes, allowing it to be targeted at cancer cells [104]. tion methods for membrane vesicles is the lack of These membranes can be used to coat nanocarriers to precise quantification. The outcome of PEGylation may improve drug delivery efficiency. It was discovered that be dependent on the compactness of PEG on the vesicles. PLGA nanocarriers coated with RBC-platelet mem- As a next step, researchers should establish standard pro- brane have a longer blood circulation time and better cedures for PEGylation of the cell membrane. binding to MDA-MB231 breast cancer cells than plain PLGA nanoparticles [103]. Another study used homo- Cell membrane hybridization typic targeting by fusing cancer cell membranes with It is possible to create a hybrid cell membrane by fus- RBC membranes [105]. The hybridized MCF7-RBC ing two parent cell membranes. These cell membranes membrane-coated nanocarriers were found to be highly have both parental cell membrane properties. Hybrid effective in terms of photothermal effect and accumula - cell membranes can synergistically carry out complex tion at tumor site in MCF7 tumor-bearing mice. This behaviors. Several studies have used hybrid cell mem- study established that the protein proportion of dual branes to coat synthetic nanocarriers [101, 102]. For membranes was a significant predictor of homotypic Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 10 of 21 impact and blood retention. To achieve the best perfor- cancer [117]. Plain mesoporous nanocarriers have a short mance, the ideal proportion of the two membranes must half-life and nonspecific macrophage uptake. To fight be found empirically. Not only may hybrid membranes be against cancer, the RBC membrane coating decreases formed by fusing two cell membranes together, but they non-specific uptake and increases blood circulation time can also be formed by fusing a cell membrane and a lipo- while combining phototherapeutic and chemotherapeu- some together. Pitchaimani et  al. reported a nanocarrier tic effects (Fig. 4). coated with a hybridized membrane of the natural killer Modification of RBC membranes with specific ligands cell membranes and liposomes [106]. The hybridization can improve delivery to target tissues. For example, when of liposome membranes in this approach enables the RGDyK peptide was inserted into the RBC membrane incorporation of several lipid components of liposomes used for coating of drug nanocrystals, they had a bet- into the cell membrane. ter distribution to tumors and antitumor efficacy than nanocrystals coated with unmodified RBC membrane or Pure cell membrane used in nanocarrier coating plain nanocrystals [97]. The CDX peptide derived from Red blood cells the neurotoxin was also used for the modification of RBC RBCs have attracted considerable interest as a biomate- membranes to target brain tissues [115]. The CDX pep - rial for nanocarriers coating [83]. In humans, RBCs have a tide was anchored to RBC membranes by streptavidin– short lifespan of up to 120 days. This short-lived property biotin. In a glioma mouse model, CDX peptide added of RBCs makes them an excellent source of membrane for to RBC membranes increased brain delivery. Zhou et al. coating nanocarriers. RBCs have a significant role in the chemically rooted hyaluronidase onto the surface of RBC removal of pathogens from the body via oxycytosis dur- membranes via bifunctional linker succinimidyl-[(N- ing the transportation of oxygen [107]. RBCs also express maleimidopropionamido)-polyethyleneglycol] ester to the ‘don’t eat me’ marker CD47, which binds to the improve tissue penetration [96]. The modification of RBC macrophage-expressed signal-regulatory protein α pre- membranes did not affect their pharmacokinetics and venting it from being taken up [108]. Therefore, the use hyaluronidase also showed its activity as usual. of an RBC membrane to coat the nanocarrier improves the detoxification process, the removal of pathogens, White blood cells and long-term circulation. Because of these properties, White blood cells (WBCs) are colorless, nucleated spher- the RBC membrane can be used for coating a variety of ical blood cells that influence disease progression. Nano - nanocarriers to deliver drugs targeting breast cancer carriers surface engineered with a WBC membrane have and colon cancer [108–111]. However, RBC membrane been widely used as anticancer drug carriers in recent can also be functionalized with iRGD peptide and folate years due to their immune escape and active targeting receptor to target breast cancer [112, 113]. For targeting abilities [118]. The most used WBCs for surface engineer - the brain, targeting ligands such as T7, cRGD peptide, ing of nanocarriers are neutrophils and macrophages. CDX peptide, and NGR peptide are incorporated into Neutrophils are the first immune cells to respond to the RBC membrane [97, 114, 115]. Coating nanocarriers tumours or infection and are closely linked to tumor pro- taking in anticancer drugs, photodynamic or photother- gression, making them ideal carriers of antitumor drugs. mal agents with RBC membranes can be used to address They are activated by chemokines or cytokines like inter - the problem of short blood retention time. Recently, a feron-gamma, interleukin 8, granulocyte–macrophage study reported melanin nanocarriers coated with RBC colony-stimulating factor, and tumour necrosis factor α membrane for effective photothermal cancer therapy which direct them to the inflammation or infection site [116]. They observed that melanin nanocarriers coated [119]. It has been shown that conformational variations with RBC membrane had higher photo thermal efficacy in integrins such as L-selectin, P-selectin, macrophage-1 in  vivo than bare melanin nanocarriers due to improved antigen, LFA-1, and VLA-4 also support neutrophil blood retention and tumor site accumulation. RBC mem- mobilization via extravasation from blood vessels [120]. branes have also been coated on iron oxide nanomaterials Therefore, the neutrophil membrane can be used for sur - capable of photothermal conversion [111]. The iron oxide face engineering of nanocarriers to target breast cancer, clusters coated with RBC membrane retain their pho- circulating tumour cells, lung cancer, and premetastatic tothermal properties while being less absorbed by mac- niches [25, 50, 121]. Zhao et  al. reported a biomimetic rophages. After intravenous injection, iron oxide clusters nanocarrier (PTX-CL/NEs) prepared by coating PTX- coated with RBC membrane showed less liver distribu- loaded liposomes with neutrophil membranes [122]. tion and more tumor accumulation in mice. Mesoporous PTX-CL/NEs successfully target tumor sites, release nanocarriers encapsulating doxorubicin have also been drugs, and inhibit tumor growth and recurrence. Cao coated with RBC membranes for photochemotherapy of et  al. surface engineered Celastrol-loaded PEG-PLGA L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 11 of 21 Fig. 4 a Curves of tumor volume in A549 tumor-bearing mice treated with various agents. b Curves of body weight of mice in each group. c Images of tumors dissected on the 13th day following photothermal treatment, as well as a comparison of each group’s tumor weight. d Hematoxylin and eosin staining images of major organs and tumor tissues dissected on the 13th day following photothermal treatment. Reproduced with permission from [116] Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 12 of 21 nanocarriers with neutrophil membranes [123]. Coating atherosclerotic sites by platelet membrane-coated nano- with neutrophil membranes allowed nanocarriers to pick carriers. So, platelet membrane coating enables nanocar- up by chemokines, pass through the blood-pancreas bar- riers to escape from macrophages and selectively bind rier, and reach the tumor site. Although neutrophil mem- injured vessels and tumour tissues. Because of these branes are rich in targeting content and fast to pick up properties, platelet membrane coated nanocarriers can by chemokines, they are preferred to use in acute treat- be used to target breast cancer lung metastasis and cir- ment situations [124]. In the case of allogeneic blood as culating tumour cells [57, 75]. When using nanocarriers a source of WBC membranes, infectious disease screen- coated with platelet membranes, it is suggested to focus ing and blood type compatibility are required because the on CD47 receptor integrity. A functional change in the WBCs are extremely diverse [125] (Fig. 5). CD47 receptor may affect biodistribution and pharma - Macrophages are classified as M1 or M2 depending on cokinetics of nanocarriers. Nanocarriers coated with their activation state. M2 macrophages reduce inflamma - platelet membranes should not be used in patients with tion, suppress the immune system, and promote tumour autoimmune diseases. Platelet autoantibodies may form growth, whereas M1 macrophages cause inflammation, immune complexes with nanocarriers [131]. stimulate the immune system, and extinguish tumour tis- In recent years, the number of platelet membrane sue [126]. M1 macrophages’ antitumor effect is derived coated drug delivery systems has increased rapidly due from surface markers like CD86, CD80, and MHC-II. to their easy extraction, purification, and accumulation Therefore, macrophage membrane-coated nanocarriers at cancer sites [132]. Rong et  al. reported a nanocarrier have been widely employed for developing antitumour of platelet membrane coated black phosphorus quantum nanocarriers targeting breast cancer and lung metas- dots carrying hederagenin (PLT@BPQDsHED) [133]. tasis of breast cancer [22, 35, 127]. The microenviron - PLT@BPQDs-HED had a stronger fluorescence signal at ment of cancer affects macrophages, so their antitumor the cancer site and a higher retention rate than the con- effect is often enhanced by administrating macrophages trol group after 48  h. A higher efficiency of drug deliv - with other therapies. Hu et  al. synthesized biomimetic ery is achieved by PLT@BPQDs-HED because selectin nanocarriers [(C/I)BP@B-A(D)&M1m] that were encap- on the platelet membrane specifically attaches to the sulated in the M1 macrophage membrane [128]. Numer- CD44 receptor overexpressed in cancer tissue. Platelets ous molecules involved in over expression of major are much more related to cancer cells, and the nanocar- histocompatibility complex (MHC) and costimulatory riers that are wrapped into platelet membranes avoid signal transduction on the cell membrane enabled (C/I) clearance by the immune system and specifically target BP@B-A(D)&M1m to target cancer tissues effectively. cancer tissue via the proteins on the membrane surface. When combined with laser irradiation, (C/I)BP@B- Platelet membrane-coated drug delivery systems have the A(D)&M1m efficiently released drugs at the site of appli - potential to be used in combination with immunotherapy cation. Liu et  al. synthesized a mixed micelle containing and phototherapy. Wu et al. wrapped nanocarriers com- bilirubin (ROX-responsive) and chlorin e6 (photosen- prising the anticancer drug and polypyrrole into platelet sitizer), loaded with paclitaxel dimer, and wrapped into membranes [134]. Platelet membrane enables the drug a macrophage membrane. By co-delivering paclitaxel delivery system to escape from immune systems and tar- dimer and Ce6, these nanocarriers effectively combine get the cancer tissue, laser irradiation triggers polypyr- photodynamic and chemotherapy therapy. Macrophage role to cause hyperthermia and ablate the cancer cells, membranes can shield drugs from being taken up by and anticancer drugs are also discharged from the nano- macrophages, which increases the likelihood of nanocar- carriers to destroy the cancer tissue. riers being absorbed and retained by tumor cells. Cancer cell Platelet Cancer is described as abnormal cell growth that could Platelets are nucleate cells of blood produced by mega- lead to metastasis. Cancerous cells’ membrane display a karyocyte fragmentation and are involved in tumor variety of tumour-specific adhesion and antigen moieties. metastasis, thrombosis, and blood coagulation [129]. There are a wide range of molecules involved in cell–cell Platelet membranes have the ability to escape phago- and cell–matrix adhesion, such as mucoprotein-1, epi- cytosis in systemic circulation. Like RBCs, the platelet thelial adhesion moieties, lymphocyte-homing recep- membrane has CD47 receptors. CD47 receptors interact tors, galectin-3, integrins, and cadherins [36, 135, 136]. with regulatory proteins that inhibit macrophage recep- Cancer cells possess properties that collectively serve a tors and can affect the pharmacokinetics of encapsu - self-protective function, such as homotypic cell adhesion lated drugs. Platelet glycoproteins may also interact with and immune system evasion [137]. Since these cells have collagen-rich plaque [130], assisting in the targeting of unique characteristics, their membranes have gained L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 13 of 21 Fig. 5 Antitumor efficacy of neutrophil membrane-coated nanocarriers in mice. A Images of mice after i.v. injections of Dil stain, Dil stain loaded PEG-PLGA nanocarriers, neutrophil membrane-coated Dil stain loaded PEG-PLGA nanocarriers. B Images of major organs and tumors after i.v. injections at 24 h, C average tumor volumes following various treatments over time, (D) morphology of tumors after 35 days, (E) variations in body weight, and (F) variations in tumor weight each treatment group over time [123] Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 14 of 21 popularity as coating stuff for nanocarriers. The dis - TGF-b1 and PD-ligand 1 expression in the tumor envi- persed membrane of cancer cells on nanocarriers allows ronment. Furthermore, T cell membrane-coated nano- various characteristics of cancer cells to be introduced to carriers improved dacarbazine delivery and enhanced the nanocarriers for targeting homotypic tumours and apoptosis of tumor cells. Ma et  al. reported the devel- developing personalized cancer therapy [66, 138]. Metal opment of a nanocarrier composed of mesoporous oxide nanoparticles, gelatin particles, mesoporous silica, silica holding IR780 nanoparticles wrapped into the and PLGA nanocarriers have all been wrapped into can- membranes of chimeric antigen receptor T cells (CAR- cer cell membranes and used to deliver anticancer drugs T) to exclusively target hepatocellular carcinoma cells [24, 72, 139, 140]. (HCCs) expressing GPC3 [85]. They engineered the Membranes of cancer cells have the feature of homolo- CAR-T cell nanocarrier in such a way that it could detect gous targeting that can be used for targeting homologous GPC3-expressing HCCs. The results demonstrated that toumors [24]. In this respect, iron oxide nanocarriers NP-coated CAR-T cell membranes were more effective were coated with HeLa cell and UM-SCC-7 membranes. at targeting HCC cells in  vivo and in  vitro than IR780- When these coated nanocarriers were allowed to incu- loaded mesoporous silica. CAR-T cell therapy is a newer bate with HeLa, HepG2, UM-SCC-7, and COS7 cells. The blood cancer treatment. Ex  vivo CAR-T cells are pro- coated nanocarriers showed a high affinity towards HeLa duced by genetically modifying TCR to recognize an cells and UM-SCC-7 cells. They could also self-target a antigen without antigen presentation. Ex  vivo-amplifier homologous tumor and effectively restrain tumor growth CAR-T cells are then reinfused into hematological can- in vivo. Some studies also reported the blood–brain bar- cer patients. The FDA has approved CAR-T cell targeting rier crossing ability of cancer cell membranes [141, 142]. of the CD19 antigen for the treatment of relapsed/refrac- For example, nanoparticles of polycaprolactone/F68 were tory diffuse large B-cell lymphoma or acute lymphoblas - coated with secondary brain cancer cell membranes and tic leukemia. then loaded with indocyanine green, a photothermal and imaging agent [141]. Intravenous injection of these Dendritic cells nanocarriers into mice bearing U87MG-Luc glioma cells Dendritic cells (DCs) are immune cells that gather showed high distribution in the brain. Similarly, PEG- around cancer cells due to immune signals (such as path- PLGA nanocarriers coated with MDA-MB-831 cancer ogen-associated molecular patterns and proinflamma - cell membrane were investigated for use in treating brain tory cytokines). They transfer tumor-associated antigens cancer [142]. They found that the accumulation of coated to lymph nodes to establish communication with naive nanocarriers in the brain was higher than uncoated T cells for differentiation into attack cancer cells and nanocarriers. mature T cells [146]. For this reason, designing tumor immunotherapy around DCs characteristics is a prom- T cells ising approach. However, issues like complex prepara- T cells play an important role in adaptive immune tion methods, short efficacy periods, and high cost still responses [143]. T cells need antigen priming through need to be addressed [147]. DC membranes contain a specific T-cell receptor (TCR) for activation. The den - components like DC-originating molecules and can tar- dritic cells (DCs) possess the MHC-antigen complex get and stimulate the immune systems of their source that engages with the TCR and activates T cells. Acti- cells [148]. It has been shown that CD40/CD80/CD83/ vated naive T cells become regulatory or effector T cells, CD86 are upregulated on the DC membranes as co-stim- depending on the DC-T cell immune synapse context. ulatory receptors [149]. The binding of these molecules Effector T cells scavenge and kill cancerous or virus- to their respective receptors on T-cells activates DCs to infected cells in the bloodstream. Moreover, T cells can produce cytokines such as IL-10, IL-12, and interleukin also mature into memory T cells, which offer long-lasting that distinguish T cells into their anti-inflammatory or protection against foreign bodies that activated them. pro-inflammatory subsets. Therefore, DC membranes Therefore, T cell membranes coated nanocarriers can be coated nanocarriers can be used to target prostate can- used to target gastric cancer, liver cancer, and tumour tis- cer and ovarian cancer [150, 151]. Cheng et  al. reported sues [85, 92, 144]. an IL-2-loaded PLGA nanocarrier warped in membranes T cell membranes were used to wrap PLGA nanocar- derived from DCs [151]. The DCs derived membranes riers loaded with dacarbazine [145]. In this study, T cell provide unique and potent stimulatory signals and sus- membranes were extracted from the EL4 cell line and tain a strong T-cell response due to their intact surface incubated with PLGA nanocarriers loaded with dacar- proteins. The nano-dimensions of this carrier may be a bazine. T cell membrane-coated nanocarriers were able significant contributor to the T cell response by elimi - to bypass tumor immune suppression and neutralize nating spatial barriers throughout antigen presentation. L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 15 of 21 Zhang et  al. used a combination of a nanocarrier-based He et al. joined a leukocyte membrane with a cancer cell antigen delivery system and photochemical internaliza- membrane to increase the targeting potential of HMCNs. tion to induce tumor-specific cytotoxic T cells in their The leutusome was produced by fusing together the study [152]. It was demonstrated that the combination membranes of leukocytes, tumor cells, and liposomal of a hydrophobic photosensitizer (Pheophorbide A) and nanocarriers simultaneously [157]. Encapsulation of polyethyleneimine possessed the ability to evade endoso- paclitaxel (PTX) with leutusomes significantly  reduced mal degradation while also enabling near-infrared imag- tumor development without causing systemic damage ing. Moreover, by grafting the synthesized complex onto (in vivo), suggesting that selective taken up of leutusomes ovalbumin, a model antigen, light-sensitive nanocarriers by tumor cells. After 48  h, leutusomes labeled with DIR were formed. displayed substantial fluorescence in tumor sites that were 9.3-fold larger than those in the control. The lipo - Hybrid membrane used in nanocarrier coating somal NPs accumulation from leukocytes or cancer cells Hybrid membranes can be used to combine the prop- was 2.7-fold and 4.4-fold more in the tumor, respectively, erties of a variety of cell membranes and optimize their than in the control. Additionally, the study indicated function [101]. In general, hybrid membrane coated that coating outside of the cores or incorporation into nanocarriers (HMCNs) more specifically interact with liposomal nanocarriers had no effect on the unique fea - the cancer environment, resulting in improved specific tures of different cell membranes. These composite bio - targeting, minimizing non-specific interactions with mimetic nanocarriers outperform solid tumour homing abundant proteins and cellular components, and opti- and have a longer circulation time due to surface markers mizing specific biological roles [153]. Moreover, a hybrid expressed on both cell types. membrane incorporates at least two distinct biological Sun et  al. developed a cancer cell-RBC hybrid mem- activities. One is a competence for targeting, whereas brane coated gold nanocage loaded with doxorubicin the other refers to inherent properties conferred by the to treat breast cancer via chemotherapy, photothermal membranes of a source cell. The targeting potential is therapy, and radiotherapy [158]. Homological targeting primarily comprised of homologous targeted delivery of the cancer cell membrane and reduced clearance by to tumor sites via DC membranes and cancer cell mem- the RBC membrane made the HMCNs particularly effec - branes, specific tumor targeting via PLT membranes, the tive in accumulating in tumor sites. Macrophages have capability of tumor targeting enhancement via mem- been associated with the early dispersion of cancer and branes of stem cells, and circulating tumor cells target- hence have a substantial effect on prolonging metastasis ing via WBC and PLT membranes [75, 154–156]. The throughout the progression of cancer. Gong et  al. devel- latter biological function types mainly include prolonga- oped a hybrid membrane composed of macrophages and tion of blood circulation via PLT and RBC membranes; cancer cells coated with doxorubicin-loaded PLGA nano- specific adherence to injured vessels via PLT membranes; carriers for use in breast cancer treatment to specifically immune evasion via PLT and WBC membranes; toxin target lung metastases [159]. Since RAW264.7 membrane neutralization and absorption via RBC and macrophage exhibits enhanced expression of high integrin α4β1, the membranes; and activation of the immune system via resultant HMCNs demonstrate remarkable membrane- bacterial outer membranes, cancer cell membranes and derived features, which include the capacity to target immune cell membranes. Due to the membrane combi- homologous cancer cells and improved particular meta- nation, HMCNs can achieve maximum functionality in static targeting potential. The metastatic nodule numbers diverse biomedical fields. in the lung were reduced by about 88.9% after the therapy The leukocyte membrane is considered a naturally of lung metastases derived from breast cancer, which occurring coating material with the biomimetic potential, performed better than the pure CMCNs. This hybrid capable of evading immune system capture and inflam - membrane derived platform demonstrates promise as a matory targeting via inducing inflammation via special - biomimetic nanoplatform for the metastasis treatment of ized ligand-receptor interaction [121]. Vectors that are breast cancer. similar to leukocytes could continue their capabilities, He and Su’s group previously described the use of such as inhibiting particle phagocytosis and opsoniza- HMCNs based on RBC and retinal endotheliocyte mem- tion, facilitating the transportation over the endothelial branes for non-invasive therapy of choroidal neovas- layer while avoiding the lysosomal pathway and thereby cularization [160]. The RBC and retinal endotheliocyte delaying the clearance by the liver [27]. However, a drug membranes fusion provide protection to the nanocar- delivery system based on a single leukocyte membrane rier against phagocytosis while also giving the potential is incapable of achieving adequate therapeutic efficiency to the HMCNs to bind with vascular endothelial growth because of its incapability towards tumor targeting. Thus, factors, enhancing their potential to target choroidal Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 16 of 21 neovascularization regions actively. particularly, the anti- biocompatibility. Platelet membranes are highly sensi- VE-cadherin antibody suppressed the fluorescent signals tive, so finding an appropriate loading scheme to ensure in HMCNs-treated cells, demonstrating that the ability of adequate drug loading and reliable delivery to the target self-targeting is dependent on surface binding molecules tissue is challenging. The toxicity and stability of modi - (N- and VE-cadherin) expression on the retinal endo- fied membranes must also be studied, especially as nano - theliocyte membrane [161]. The substantial fluorescence carriers for cancer therapy. To achieve the desired dose colocalization of angiogenic retinal endotheliocyte mem- and release profile, the drug loading method should be branes and HMCNs in the tube formation experiment chosen carefully [163]. also indicated the nanocarriers’ targeting ability. Fur- Moreover, a complete understanding of the mecha- thermore, using a quantitative examination of the mean nism of transporting cell membranes extracted from dif- fluorescence intensity, the group treated with HMCNs ferent sources in  vivo is unknown and requires further drastically decreased damage area and choroidal neovas- research. For example, therapeutic molecules delivered cularization leakage in contrast to the group treated with by white cell membrane carriers may activate immune pure CMCNs in a choroidal neovascularization mouse system components and cause inflammation [164]. When model induced by laser. In conclusion, dual-fused mem- cancer cell membrane is used, it may cause cancer in the brane-based nanocarriers offer significant advantages body if the parent cancer cells’ genetic material is not over currently available invasive therapies. completely removed. Procedures for purifying and char- acterizing cell membranes are not consistent and differ Challenges and future directions from laboratory to laboratory, causing confusion about Numerous advantages have been reported for CMCNs, the physicochemical features of the cell membrane. So, particularly in terms of biocompatibility and targeting. it is necessary to share the scientific data and develop a Synthetic DDSs currently available are basically foreign standardized procedure for cell membrane quality con- substances with the potential for immunogenicity and trol that is highly repeatable. Nanocarriers wrapped into toxicity. Whereas cell membranes are endogenous, they cell membranes and extracellular vesicles can target can- are considered biocompatible and perform a variety of cer tissues crossing biological barriers. Some cells can be biological functions like the source cell. However, cer- used to both extract membranes and isolate extracellular tain issues must be resolved before these carriers can vesicles to transport drugs. While it is relatively simple continue to evolve and move from the laboratory to the to extract and prepare the cell membrane, the targeting clinic. ability may be compromised due to protein loss during The first and most important question to be addressed membrane extraction. However, extracellular vesicles is about the yield of cell membranes and extracellu- are difficult to prepare, they generally retain all mem - lar vesicles. Not only do existing separation technolo- brane components, giving them excellent targeting ability gies produce a negligible amount of cell membranes [165]. As a result, the appropriate carrier must be chosen and extracellular vesicles, but they are also prohibitively according to the experiment’s objective in order to maxi- expensive for large-scale production. As a result, more mize the therapeutic effect. sophisticated large-scale manufacturing methods are required to continue expanding the application of cell Conclusions membrane. In recent years, to address the yield issue, The development of therapeutics derived from cell extensive work has been carried out on techniques membrane material is a rapidly growing field of which are used for generating artificial vesicles when research that is particularly appealing because it the membrane is ruptured via extrusion. For example, involves an organic cellular networking system. Biomi- the same number of THP-1 cells yield more than twice metic technology has the advantage of taking advan- as many simulated exosomes as natural exosomes, and tage of the natural mechanisms of living matter, but the drug encapsulating and releasing rates of the simu- it is also a double-edged sword. It is difficult to know lated exosomes are also higher [162]. The extraction which components, out of the multiple factors, confer and purification procedures must also be revised and membrane functionality, and so the ratio of each com- optimized, as many cells must still be cultured to obtain ponent needs to be modified as needed. To develop an adequate number of membranes, and the prepara- drug-containing membrane-coated carriers, a simi- tion procedure must still be simplified [118]. For RBCs larly and standardized manufacturing process will be membrane-coated nanocarriers that lack a targeting abil- required. Despite the difficulties associated with pro - ity, the membranes must be modified to reach the tar - cessing variables, manufacturing, and quality control, get site for therapeutic cargo release, but this will likely vesicles derived from natural cells have the advantage change the membrane’s original structure and reduce its of being bioactive, reflecting the features of the parent L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 17 of 21 3. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocar- cells. Although membrane-coated nanocarriers face riers as an emerging platform for cancer therapy. Nat Nanotechnol. numerous challenges, a powerful advantage of ‘mimick- 2007;2:751–60. ing nature’ overrides many disadvantages of traditional 4. Mitragotri S, Burke PA, Langer R. Overcoming the challenges in adminis- tering biopharmaceuticals: formulation and delivery strategies. Nat Rev DDSs and offers a more efficient approach for cancer Drug Discov. 2014;13:655–72. treatment. With the rapid advancement of nanotech- 5. Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: nology, proteomics, bioinformatics, pharmacology, and passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Contr Rel. 2010;148:135–46. material science, it is expected that the combination 6. Ekladious I, Colson YL, Grinstaff MW. Polymer–drug conjugate of DDSs and cells will overcome numerous obstacles, therapeutics: advances, insights and prospects. Nat Rev Drug Discov. revolutionize current medical technology, and open up 2019;18:273–94. 7. Zhou M, Huang H, Wang D, Lu H, Chen J, Chai Z, Yao SQ, Hu Y. Light- new avenues for targeted cancer therapy. triggered PEGylation/dePEGylation of the nanocarriers for enhanced tumor penetration. Nano Lett. 2019;19:3671–5. Acknowledgements 8. Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to Authors are grateful to Hospital of Hangzhou Medical College for providing clinical applications. Adv Drug Deliv Rev. 2013;65:36–48. necessary facilities. 9. Moradi Kashkooli F, Soltani M, Souri M. Controlled anti-cancer drug release through advanced nano-drug delivery systems: static and Authors’ contributions dynamic targeting strategies. J Contr Rel. 2020;327:316–49. WL, CY, YW, GR, XH, XT, and SW wrote different sections of the manuscript. WL, 10. Shreffler JW, Pullan JE, Dailey KM, Mallik S, Brooks AE. Overcoming hur - CY, and SW edited the manuscript. All authors read and approved the final dles in nanoparticle clinical translation: the influence of experimental manuscript. design and surface modification. Int J Mol Sci. 2019;20:6056. 11. Walsh G. Biopharmaceutical benchmarks 2018. Nat Biotechnol. Funding 2018;36:1136–45. This study was supported by the Foundation of Science Technology Depart- 12. DeLoach J, Barton C, Culler K. Preparation of resealed carrier erythro- ment of Zhejiang Province (No. LGF22H080012, LY19H160037, LGF18H160025) cytes and in vivo survival in dogs. Am J Vet Res. 1981;42:667–9. and the funds from Zhejiang Medical Technology Plan Project (No. 13. Pang L, Zhang C, Qin J, Han L, Li R, Hong C, He H, Wang J. A novel strat- 2020KY052). egy to achieve effective drug delivery: exploit cells as carrier combined with nanoparticles. Drug Deliv. 2017;24:83–91. Availability of data and materials 14. Jiang X, Rocker C, Hafner M, Brandholt S, Dorlich RM, Nienhaus GU. Not applicable. Endo-and exocytosis of zwitterionic quantum dot nanoparticles by live HeLa cells. ACS Nano. 2010;4:6787–97. Declarations 15. Hu C-MJ, Zhang L, Aryal S, Cheung C, Fang RH, Zhang L. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic Ethics approval and consent to participate delivery platform. Proc Nat Acad Sci. 2011;108:10980–5. Not applicable. 16. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular Consent for publication drug targeting. Adv Enzyme Regul. 2001;41:189–207. All authors have approved the final draft of this manuscript for submission and 17. Sabu C, Rejo C, Kotta S, Pramod K. Bioinspired and biomimetic systems have given consent for the publication of identifiable details. for advanced drug and gene delivery. J Contr Rel. 2018;287:142–55. 18. Rasheed T, Nabeel F, Raza A, Bilal M, Iqbal H. Biomimetic nanostruc- Competing interests tures/cues as drug delivery systems: a review. Mater Today Chem. The authors have declared no conflict of interest. 2019;13:147–57. 19. Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune responses to viral Author details gene therapy vectors. Mol Ther. 2020;28:709–22. Department of Hematology, The Second Affiliated Hospital, College 20. von Roemeling C, Jiang W, Chan CK, Weissman IL, Kim BY. Breaking of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, People’s down the barriers to precision cancer nanomedicine. Trends Biotech- Republic of China. Department of Ultrasonography, Zhejiang Provincial nol. 2017;35:159–71. People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, 21. Gao M, Liang C, Song X, Chen Q, Jin Q, Wang C, Liu Z. Erythrocyte- Zhejiang 310014, People’s Republic of China. Phase I Clinical Research Center, membrane-enveloped perfluorocarbon as nanoscale artificial red Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical blood cells to relieve tumor hypoxia and enhance cancer radiotherapy. College, Hangzhou, Zhejiang 310014, People’s Republic of China. Depar t- Adv Mater. 2017;29:1701429. ments of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital 22. Cao H, Dan Z, He X, Zhang Z, Yu H, Yin Q, Li Y. Liposomes coated with of Hangzhou Medical College, Hangzhou, Zhejiang 310014, People’s Republic isolated macrophage membrane can target lung metastasis of breast of China. Cancer Center, Key Laboratory of Tumor Molecular Diagnosis cancer. ACS Nano. 2016;10:7738–48. and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s 23. Orbach A, Zelig O, Yedgar S, Barshtein G. Biophysical and biochemical Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, markers of red blood cell fragility. Transf Med Hemother. 2017;44:183–7. Zhejiang 310014, People’s Republic of China. 24. Zhu J-Y, Zheng D-W, Zhang M-K, Yu W-Y, Qiu W-X, Hu J-J, Feng J, Zhang X-Z. Preferential cancer cell self-recognition and tumor self-targeting by Received: 22 October 2021 Accepted: 7 January 2022 coating nanoparticles with homotypic cancer cell membranes. Nano Lett. 2016;16:5895–901. 25. Kang T, Zhu Q, Wei D, Feng J, Yao J, Jiang T, Song Q, Wei X, Chen H, Gao X. Nanoparticles coated with neutrophil membranes can effectively treat cancer metastasis. ACS Nano. 2017;11:1397–411. References 26. Spicer JD, McDonald B, Cools-Lartigue JJ, Chow SC, Giannias B, Kubes 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer P, Ferri LE. Neutrophils promote liver metastasis via Mac-1-mediated statistics. CA: Cancer J Clin. 2011;61:69–90. interactions with circulating tumor cells. Can Res. 2012;72:3919–27. 2. Chen W, Zheng R, Zeng H, Zhang S, He J. Annual report on status of 27. Parodi A, Quattrocchi N, Van De Ven AL, Chiappini C, Evangelopoulos cancer in China, 2011. Chin J Cancer Res. 2015;27:2. M, Martinez JO, Brown BS, Khaled SZ, Yazdi IK, Enzo MV. Synthetic Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 18 of 21 nanoparticles functionalized with biomimetic leukocyte membranes 50. Deng G, Sun Z, Li S, Peng X, Li W, Zhou L, Ma Y, Gong P, Cai L. Cell- possess cell-like functions. Nat Nanotechnol. 2013;8:61–8. membrane immunotherapy based on natural killer cell membrane 28. Chugh V, Vijaya Krishna K, Pandit A. Cell membrane-coated mimics: a coated nanoparticles for the effective inhibition of primary and absco - methodological approach for fabrication, characterization for thera- pal tumor growth. ACS Nano. 2018;12:12096–108. peutic applications, and challenges for clinical translation. ACS Nano. 51. An X, Salomao M, Guo X, Gratzer W, Mohandas N. Tropomyosin modu- 2021;15:17080–123. lates erythrocyte membrane stability. Blood. 2007;109:1284–8. 29. Engelman DM. Membranes are more mosaic than fluid. Nature. 52. Chakraborty S, Doktorova M, Molugu TR, Heberle FA, Scott HL, 2005;438:578–80. Dzikovski B, Nagao M, Stingaciu L-R, Standaert RF, Barrera FN. How 30. Bucior I, Scheuring S, Engel A, Burger MM. Carbohydrate–carbohydrate cholesterol stiffens unsaturated lipid membranes. Proc Natl Acad Sci. interaction provides adhesion force and specificity for cellular recogni- 2020;117:21896–905. tion. J Cell Biol. 2004;165:529–37. 53. Virlan MJR, Miricescu D, Radulescu R, Sabliov CM, Totan A, Calenic B, 31. Simons K, Vaz WL. Model systems, lipid rafts, and cell membranes. Annu Greabu M. Organic nanomaterials and their applications in the treat- Rev Biophys Biomol Struct. 2004;33:269–95. ment of oral diseases. Molecules. 2016;21:207. 32. Casares D, Escribá PV, Rosselló CA. Membrane lipid composition: effect 54. Anselmo AC, Mitragotri S. A review of clinical translation of inorganic on membrane and organelle structure, function and compartmentali- nanoparticles. AAPS J. 2015;17:1041–54. zation and therapeutic avenues. Int J Mol Sci. 2019;20:2167. 55. Ehlerding EB, Chen F, Cai W. Biodegradable and renal clearable inor- 33. Kim J, Koo B-K, Knoblich JA. Human organoids: model systems for ganic nanoparticles. Adv Sci. 2016;3:1500223. human biology and medicine. Nat Rev Mol Cell Biol. 2020;21:571–84. 56. Su S, Kang PM. Systemic review of biodegradable nanomaterials in 34. Andrews RK, López J, Berndt MC. Molecular mechanisms of platelet nanomedicine. Nanomaterials. 2020;10:656. adhesion and activation. Int J Biochem Cell Biol. 1997;29:91–105. 57. Ye H, Wang K, Wang M, Liu R, Song H, Li N, Lu Q, Zhang W, Du Y, Yang W. 35. Si J, Shao S, Shen Y, Wang K. Macrophages as active nanocarri- Bioinspired nanoplatelets for chemo-photothermal therapy of breast ers for targeted early and adjuvant cancer chemotherapy. Small. cancer metastasis inhibition. Biomaterials. 2019;206:1–12. 2016;12:5108–19. 58. Xu C, Liu W, Hu Y, Li W, Di W. Bioinspired tumor-homing nanoplatform 36. Sökeland G, Schumacher U. The functional role of integrins during for co-delivery of paclitaxel and siRNA-E7 to HPV-related cervical malig- intra-and extravasation within the metastatic cascade. Mol Cancer. nancies for synergistic therapy. Theranostics. 2020;10:3325. 2019;18:1–19. 59. Zhang Q, Dehaini D, Zhang Y, Zhou J, Chen X, Zhang L, Fang RH, Gao W, 37. Bose RJ, Paulmurugan R, Moon J, Lee S-H, Park H. Cell membrane- Zhang L. Neutrophil membrane-coated nanoparticles inhibit synovial coated nanocarriers: the emerging targeted delivery system for cancer inflammation and alleviate joint damage in inflammatory arthritis. Nat theranostics. Drug Discov Today. 2018;23:891–9. Nanotechnol. 2018;13:1182–90. 38. Evangelopoulos M, Parodi A, Martinez JO, Yazdi IK, Cevenini A, van de 60. Tang J, Shen D, Caranasos TG, Wang Z, Vandergriff AC, Allen TA, Hensley Ven AL, Quattrocchi N, Boada C, Taghipour N, Corbo C. Cell source MT, Dinh P-U, Cores J, Li T-S. Therapeutic microparticles functionalized determines the immunological impact of biomimetic nanoparticles. with biomimetic cardiac stem cell membranes and secretome. Nat Biomaterials. 2016;82:168–77. Commun. 2017;8:1–9. 39. Kaneti L, Bronshtein T, Malkah Dayan N, Kovregina I, Letko Khait N, 61. Li L-L, Xu J-H, Qi G-B, Zhao X, Yu F, Wang H. Core–shell supramolecular Lupu-Haber Y, Fliman M, Schoen BW, Kaneti G, Machluf M. Nanoghosts gelatin nanoparticles for adaptive and “on-demand” antibiotic delivery. as a novel natural nonviral gene delivery platform safely targeting ACS Nano. 2014;8:4975–83. multiple cancers. Nano Lett. 2016;16:1574–82. 62. Gao C, Lin Z, Jurado-Sánchez B, Lin X, Wu Z, He Q. Stem cell membrane- 40. Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ. Therapeutic cell coated nanogels for highly efficient in vivo tumor targeted drug engineering with surface-conjugated synthetic nanoparticles. Nat Med. delivery. Small. 2016;12:4056–62. 2010;16:1035–41. 63. Zhai Y, Ran W, Su J, Lang T, Meng J, Wang G, Zhang P, Li Y. Traceable 41. Van Deun J, Roux Q, Deville S, Van Acker T, Rappu P, Miinalainen I, Heino bioinspired nanoparticle for the treatment of metastatic breast cancer J, Vanhaecke F, De Geest BG, De Wever O. Feasibility of mechanical via NIR-trigged intracellular delivery of methylene blue and cisplatin. extrusion to coat nanoparticles with extracellular vesicle membranes. Adv Mater. 2018;30:1802378. Cells. 2020;9:1797. 64. Rao L, Wang W, Meng Q-F, Tian M, Cai B, Wang Y, Li A, Zan M, Xiao F, Bu 42. Parrow NL, Violet P-C, Tu H, Nichols J, Pittman CA, Fitzhugh C, Fleming L-L. A biomimetic nanodecoy traps Zika virus to prevent viral infection RE, Mohandas N, Tisdale JF, Levine M. Measuring deformability and and fetal microcephaly development. Nano Lett. 2018;19:2215–22. red cell heterogeneity in blood by ektacytometry. J Vis Exp JoVE. 65. Xie J, Shen Q, Huang K, Zheng T, Cheng L, Zhang Z, Yu Y, Liao G, Wang X, 2018;2018:56910. Li C. Oriented assembly of cell-mimicking nanoparticles via a molecular 43. Kuo Y-C, Wu H-C, Hoang D, Bentley WE, D’Souza WD, Raghavan SR. Col- affinity strategy for targeted drug delivery. ACS Nano. 2019;13:5268–77. loidal properties of nanoerythrosomes derived from bovine red blood 66. Nie D, Dai Z, Li J, Yang Y, Xi Z, Wang J, Zhang W, Qian K, Guo S, Zhu C. cells. Langmuir. 2016;32:171–9. Cancer-cell-membrane-coated nanoparticles with a yolk–shell struc- 44. Kim DS, Lee MW, Ko YJ, Jang IK, Jeon S, Na B, Chae JJ, Sung KW, Koo HH, ture augment cancer chemotherapy. Nano Lett. 2019;20:936–46. Yoo KH. Eec ff t of ex vivo culture density on CXCR7 expression in human 67. Castro CI, Briceno JC. Perfluorocarbon-based oxygen carriers: review of mesenchymal stem cells. Int J Clin Exp Med. 2016;9:10802–10. products and trials. Artif Organs. 2010;34:622–34. 45. Park JS, Suryaprakash S, Lao Y-H, Leong KW. Engineering mesenchy- 68. Zou MZ, Liu WL, Gao F, Bai XF, Chen HS, Zeng X, Zhang XZ. Artificial nat - mal stem cells for regenerative medicine and drug delivery. Methods. ural killer cells for specific tumor inhibition and renegade macrophage 2015;84:3–16. re-education. Adv Mater. 2019;31:1904495. 46. Muzykantov VR, Murciano JC, Taylor RP, Atochina EN, Herraez A. Regula- 69. Watermann A, Brieger J. Mesoporous silica nanoparticles as drug deliv- tion of the complement-mediated elimination of red blood cells modi- ery vehicles in cancer. Nanomaterials. 2017;7:189. fied with biotin and streptavidin. Anal Biochem. 1996;241:109–19. 70. Jafari S, Derakhshankhah H, Alaei L, Fattahi A, Varnamkhasti BS, Saboury 47. Wang Y, Zhang K, Qin X, Li T, Qiu J, Yin T, Huang J, McGinty S, Pontrelli AA. Mesoporous silica nanoparticles for therapeutic/diagnostic applica- G, Ren J. Biomimetic nanotherapies: red blood cell based core–shell tions. Biomed Pharmacother. 2019;109:1100–11. structured nanocomplexes for atherosclerosis management. Adv Sci. 71. Xuan M, Shao J, Zhao J, Li Q, Dai L, Li J. Cover picture: magnetic 2019;6:1900172. mesoporous silica nanoparticles cloaked by red blood cell mem- 48. Hu C-MJ, Fang RH, Wang K-C, Luk BT, Thamphiwatana S, Dehaini D, branes: applications in cancer therapy. Angew Chem Int Ed. Nguyen P, Angsantikul P, Wen CH, Kroll AV. Nanoparticle biointerfacing 2018;57:5955–5955. by platelet membrane cloaking. Nature. 2015;526:118–21. 72. Cai D, Liu L, Han C, Ma X, Qian J, Zhou J, Zhu W. Cancer cell membrane- 49. Thamphiwatana S, Angsantikul P, Escajadillo T, Zhang Q, Olson J, Luk coated mesoporous silica loaded with superparamagnetic ferroferric BT, Zhang S, Fang RH, Gao W, Nizet V. Macrophage-like nanoparticles oxide and Paclitaxel for the combination of Chemo/Magnetocaloric concurrently absorbing endotoxins and proinflammatory cytokines for therapy on MDA-MB-231 cells. Sci Rep. 2019;9:1–10. sepsis management. Proc Natl Acad Sci. 2017;114:11488–93. L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 19 of 21 73. Hao N, Yang H, Li L, Li L, Tang F. The shape effect of mesoporous silica therapeutics into cholesterol-enriched cell-membrane-derived vesicles. nanoparticles on intracellular reactive oxygen species in A375 cells. Angew Chem Int Ed. 2017;56:14075–9. New J Chem. 2014;38:4258–66. 95. Peng L-H, Zhang Y-H, Han L-J, Zhang C-Z, Wu J-H, Wang X-R, Gao J-Q, 74. Hu C-MJ, Fang RH, Copp J, Luk BT, Zhang L. A biomimetic nanosponge Mao Z-W. Cell membrane capsules for encapsulation of chemothera- that absorbs pore-forming toxins. Nat Nanotechnol. 2013;8:336–40. peutic and cancer cell targeting in vivo. ACS Appl Mater Interfaces. 75. Li J, Ai Y, Wang L, Bu P, Sharkey CC, Wu Q, Wun B, Roy S, Shen X, King 2015;7:18628–37. MR. Targeted drug delivery to circulating tumor cells via platelet 96. Zhou H, Fan Z, Lemons PK, Cheng H. A facile approach to functionalize membrane-functionalized particles. Biomaterials. 2016;76:52–65. cell membrane-coated nanoparticles. Theranostics. 2016;6:1012. 76. Meng Q-F, Rao L, Zan M, Chen M, Yu G-T, Wei X, Wu Z, Sun Y, Guo 97. Chai Z, Ran D, Lu L, Zhan C, Ruan H, Hu X, Xie C, Jiang K, Li J, Zhou J. S-S, Zhao X-Z. Macrophage membrane-coated iron oxide nanopar- Ligand-modified cell membrane enables the targeted delivery of drug ticles for enhanced photothermal tumor therapy. Nanotechnology. nanocrystals to glioma. ACS Nano. 2019;13:5591–601. 2018;29:134004. 98. Kaddah S, Khreich N, Kaddah F, Charcosset C, Greige-Gerges H. Choles- 77. Lai P-Y, Huang R-Y, Lin S-Y, Lin Y-H, Chang C-W. Biomimetic stem cell terol modulates the liposome membrane fluidity and permeability for a membrane-camouflaged iron oxide nanoparticles for theranostic hydrophilic molecule. Food Chem Toxicol. 2018;113:40–8. applications. RSC Adv. 2015;5:98222–30. 99. Chen Z, Zhao P, Luo Z, Zheng M, Tian H, Gong P, Gao G, Pan H, Liu L, Ma 78. Zhu J, Zhang M, Zheng D, Hong S, Feng J, Zhang X-Z. A universal A. Cancer cell membrane–biomimetic nanoparticles for homologous- approach to render nanomedicine with biological identity derived from targeting dual-modal imaging and photothermal therapy. ACS Nano. cell membranes. Biomacromol. 2018;19:2043–52. 2016;10:10049–57. 79. Cook TR, Zheng Y-R, Stang PJ. Metal–organic frameworks and self- 100. Song Y, Huang Z, Liu X, Pang Z, Chen J, Yang H, Zhang N, Cao Z, Liu M, assembled supramolecular coordination complexes: comparing and Cao J. Platelet membrane-coated nanoparticle-mediated targeting contrasting the design, synthesis, and functionality of metal–organic delivery of Rapamycin blocks atherosclerotic plaque development −/− materials. Chem Rev. 2013;113:734–77. and stabilizes plaque in apolipoprotein E-deficient (ApoE ) mice. 80. Hoop M, Walde CF, Riccò R, Mushtaq F, Terzopoulou A, Chen X-Z, Nanomed Nanotechnol Biol Med. 2019;15:13–24. deMello AJ, Doonan CJ, Falcaro P, Nelson BJ. Biocompatibility charac- 101. Chen H-Y, Deng J, Wang Y, Wu C-Q, Li X, Dai H-W. Hybrid cell mem- teristics of the metal organic framework ZIF-8 for therapeutical applica- brane-coated nanoparticles: a multifunctional biomimetic platform for tions. Appl Mater Today. 2018;11:13–21. cancer diagnosis and therapy. Acta Biomater. 2020;112:1–13. 81. Huang J, Shen H, Wu J, Hu X, Zhu Z, Lv X, Liu Y, Wang Y. Spine Explorer: a 102. Liang X, Ye X, Wang C, Xing C, Miao Q, Xie Z, Chen X, Zhang X, deep learning based fully automated program for efficient and reliable Zhang H, Mei L. Photothermal cancer immunotherapy by erythro- quantifications of the vertebrae and discs on sagittal lumbar spine MR cyte membrane-coated black phosphorus formulation. J Contr Rel. images. Spine J. 2020;20:590–9. 2019;296:150–61. 82. Carnovale C, Bryant G, Shukla R, Bansal V. Identifying trends in gold 103. Dehaini D, Wei X, Fang RH, Masson S, Angsantikul P, Luk BT, Zhang nanoparticle toxicity and uptake: size, shape, capping ligand, and Y, Ying M, Jiang Y, Kroll AV. Erythrocyte–platelet hybrid membrane biological corona. ACS Omega. 2019;4:242–56. coating for enhanced nanoparticle functionalization. Adv Mater. 83. Fang RH, Kroll AV, Gao W, Zhang L. Cell membrane coating nanotech- 2017;29:1606209. nology. Adv Mater. 2018;30:1706759. 104. St John AE, Newton JC, Martin EJ, Mohammed BM, Contaifer D Jr, 84. Zhang X, He S, Ding B, Qu C, Zhang Q, Chen H, Sun Y, Fang H, Long Y, Saunders JL, Brophy GM, Spiess BD, Ward KR, Brophy DF. Platelets retain Zhang R. Cancer cell membrane-coated rare earth doped nanoparticles inducible alpha granule secretion by P-selectin expression but exhibit for tumor surgery navigation in NIR-II imaging window. Chem Eng J. mechanical dysfunction during trauma-induced coagulopathy. J 2020;385:123959. Thromb Haemost. 2019;17:771–81. 85. Ma W, Zhu D, Li J, Chen X, Xie W, Jiang X, Wu L, Wang G, Xiao Y, Liu Z. 105. Sun D, Chen J, Wang Y, Ji H, Peng R, Jin L, Wu W. Advances in refunction- Coating biomimetic nanoparticles with chimeric antigen receptor T alization of erythrocyte-based nanomedicine for enhancing cancer- cell-membrane provides high specificity for hepatocellular carcinoma targeted drug delivery. Theranostics. 2019;9:6885. photothermal therapy treatment. Theranostics. 2020;10:1281. 106. Pitchaimani A, Nguyen TDT, Aryal S. Natural killer cell membrane 86. Mishra P, Jain N. Folate conjugated doxorubicin-loaded membrane infused biomimetic liposomes for targeted tumor therapy. Biomaterials. vesicles for improved cancer therapy. Drug Deliv. 2003;10:277–82. 2018;160:124–37. 87. Xuan M, Shao J, Dai L, Li J, He Q. Macrophage cell membrane cam- 107. Minasyan H. Phagocytosis and oxycytosis: two arms of human innate ouflaged Au nanoshells for in vivo prolonged circulation life and immunity. Immunol Res. 2018;66:271–80. enhanced cancer photothermal therapy. ACS Appl Mater Interfaces. 108. Wang H, Sun Y, Zhou X, Chen C, Jiao L, Li W, Gou S, Li Y, Du J, Chen G, 2016;8:9610–8. et al. CD47/SIRPα blocking peptide identification and synergistic effect 88. Michael M, Vermeren S. A neutrophil-centric view of chemotaxis. Essays with irradiation for cancer immunotherapy. J Immunother Cancer. Biochem. 2019;63:607–18. 2020;8:e000905. 89. Sekeres J, Zarsky V. 180 years of the cell: from Matthias Jakob Schleiden 109. Cao Z, Cheng S, Wang X, Pang Y, Liu J. Camouflaging bacteria by wrap - to the cell biology of the twenty-first century. In: Concepts in cell ping with cell membranes. Nat Commun. 2019;10:1–10. biology-history and evolution. Berlin: Springer; 2018. p. 7–37. 110. Liu J-M, Zhang D-D, Fang G-Z, Wang S. Erythrocyte membrane 90. Goñi FM. The basic structure and dynamics of cell membranes: An bioinspired near-infrared persistent luminescence nanocarriers for update of the Singer-Nicolson model. Biochim Biophys Acta (BBA) in vivo long-circulating bioimaging and drug delivery. Biomaterials. Biomembr. 2014;1838:1467–76. 2018;165:39–47. 91. Shi Y, Xie F, Rao P, Qian H, Chen R, Chen H, Li D, Mu D, Zhang L, Lv P. 111. Ren X, Zheng R, Fang X, Wang X, Zhang X, Yang W, Sha X. Red blood cell TRAIL-expressing cell membrane nanovesicles as an anti-inflammatory membrane camouflaged magnetic nanoclusters for imaging-guided platform for rheumatoid arthritis therapy. J Contr Rel. 2020;320:304–13. photothermal therapy. Biomaterials. 2016;92:13–24. 92. Han Y, Pan H, Li W, Chen Z, Ma A, Yin T, Liang R, Chen F, Ma Y, Jin Y. T cell 112. Rao L, Meng Q-F, Bu L-L, Cai B, Huang Q, Sun Z-J, Zhang W-F, Li A, Guo membrane mimicking nanoparticles with bioorthogonal targeting S-S, Liu W. Erythrocyte membrane-coated upconversion nanoparticles and immune recognition for enhanced photothermal therapy. Adv Sci. with minimal protein adsorption for enhanced tumor imaging. ACS 2019;6:1900251. Appl Mater Interfaces. 2017;9:2159–68. 93. Lv P, Liu X, Chen X, Liu C, Zhang Y, Chu C, Wang J, Wang X, Chen X, Liu 113. Su J, Sun H, Meng Q, Yin Q, Tang S, Zhang P, Chen Y, Zhang Z, Yu H, Li Y. G. Genetically engineered cell membrane nanovesicles for oncolytic Long circulation red-blood-cell-mimetic nanoparticles with peptide- adenovirus delivery: a versatile platform for cancer virotherapy. Nano enhanced tumor penetration for simultaneously inhibiting growth and Lett. 2019;19:2993–3001. lung metastasis of breast cancer. Adv Func Mater. 2016;26:1243–52. 94. Zhang X, Angsantikul P, Ying M, Zhuang J, Zhang Q, Wei X, Jiang 114. Fu S, Liang M, Wang Y, Cui L, Gao C, Chu X, Liu Q, Feng Y, Gong W, Yang Y, Zhang Y, Dehaini D, Chen M. Remote loading of small-molecule M. Dual-modified novel biomimetic nanocarriers improve targeting Lei et al. Journal of Nanobiotechnology (2022) 20:45 Page 20 of 21 and therapeutic efficacy in glioma. ACS Appl Mater Interfaces. gradient production and T-cell tumor infiltration. Nat Commun. 2018;11:1841–54. 2017;8:1–15. 115. Chai Z, Hu X, Wei X, Zhan C, Lu L, Jiang K, Su B, Ruan H, Ran D, Fang RH. 137. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. A facile approach to functionalizing cell membrane-coated nanoparti- Cell. 2011;144:646–74. cles with neurotoxin-derived peptide for brain-targeted drug delivery. J 138. Zhang J, Miao Y, Ni W, Xiao H, Zhang J. Cancer cell membrane coated Contr Rel. 2017;264:102–11. silica nanoparticles loaded with ICG for tumour specific photo - 116. Jiang Q, Luo Z, Men Y, Yang P, Peng H, Guo R, Tian Y, Pang Z, Yang W. thermal therapy of osteosarcoma. Artif Cells Nanomed Biotechnol. Red blood cell membrane-camouflaged melanin nanoparticles for 2019;47:2298–305. enhanced photothermal therapy. Biomaterials. 2017;143:29–45. 139. Rao L, Yu GT, Meng QF, Bu LL, Tian R, Lin LS, Deng H, Yang W, Zan M, 117. Chen W, Zeng K, Liu H, Ouyang J, Wang L, Liu Y, Wang H, Deng L, Liu YN. Ding J. Cancer cell membrane-coated nanoparticles for personal- Cell membrane camouflaged hollow prussian blue nanoparticles for ized therapy in patient-derived xenograft models. Adv Func Mater. synergistic photothermal-/chemotherapy of cancer. Adv Func Mater. 2019;29:1905671. 2017;27:1605795. 140. Jin J, Krishnamachary B, Barnett JD, Chatterjee S, Chang D, Mironchik 118. Li B, Wang F, Gui L, He Q, Yao Y, Chen H. The potential of biomimetic Y, Wildes F, Jaffee EM, Nimmagadda S, Bhujwalla ZM. Human cancer nanoparticles for tumor-targeted drug delivery. Nanomedicine. cell membrane-coated biomimetic nanoparticles reduce fibroblast- 2018;13:2099–118. mediated invasion and metastasis and induce T-cells. ACS Appl Mater 119. Rosales C. Neutrophil: a cell with many roles in inflammation or several Interfaces. 2019;11:7850–61. cell types? Front Physiol. 2018;9:113. 141. Wang C, Wu B, Wu Y, Song X, Zhang S, Liu Z. Camouflaging nanopar - 120. Morikis VA, Simon SI. Neutrophil mechanosignaling promotes integrin ticles with brain metastatic tumor cell membranes: a new strategy to engagement with endothelial cells and motility within inflamed ves- traverse blood–brain barrier for imaging and therapy of brain tumors. sels. Front Immunol. 2018;9:2774. Adv Func Mater. 2020;30:1909369. 121. He Z, Zhang Y, Feng N. Cell membrane-coated nanosized active tar- 142. Kumar P, Van Treuren T, Ranjan AP, Chaudhary P, Vishwanatha JK. In vivo geted drug delivery systems homing to tumor cells: a review. Mater Sci imaging and biodistribution of near infrared dye loaded brain-meta- Eng C. 2020;106:110298. static-breast-cancer-cell-membrane coated polymeric nanoparticles. 122. Xue J, Zhao Z, Zhang L, Xue L, Shen S, Wen Y, Wei Z, Wang L, Kong L, Nanotechnology. 2019;30:265101. Sun H. Neutrophil-mediated anticancer drug delivery for suppres- 143. Ribas A. Adaptive immune resistance: how cancer protects from sion of postoperative malignant glioma recurrence. Nat Nanotechnol. immune attack. Cancer Discov. 2015;5:915–9. 2017;12:692–700. 144. Zhang L, Li R, Chen H, Wei J, Qian H, Su S, Shao J, Wang L, Qian X, Liu B. 123. Cao X, Hu Y, Luo S, Wang Y, Gong T, Sun X, Fu Y, Zhang Z. Neutrophil- Human cytotoxic T-lymphocyte membrane-camouflaged nanoparticles mimicking therapeutic nanoparticles for targeted chemotherapy of combined with low-dose irradiation: a new approach to enhance drug pancreatic carcinoma. Acta Pharmaceut Sin B. 2019;9:575–89. targeting in gastric cancer. Int J Nanomed. 2017;12:2129. 124. Combes F, Meyer E, Sanders NN. Immune cells as tumor drug delivery 145. Um W, Ko H, You DG, Lim S, Kwak G, Shim MK, Yang S, Lee J, Song Y, Kim vehicles. J Control Rel. 2020;327:70–87. K, Park JH. Necroptosis-inducible polymeric nanobubbles for enhanced 125. Wu M, Le W, Mei T, Wang Y, Chen B, Liu Z, Xue C. Cell membrane cancer sonoimmunotherapy. Adv Mater. 2020;32:1907953. camouflaged nanoparticles: a new biomimetic platform for cancer 146. Chen DS, Mellman I. Oncology meets immunology: the cancer-immu- photothermal therapy. Int J Nanomed. 2019;14:4431. nity cycle. Immunity. 2013;39:1–10. 126. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, 147. Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, Steven NM, Esmaeili SA, Mardani F, Seifi B, Mohammadi A, Afshari JT, Sahebkar A. Kerr DJ, Young LS, Adams DH. A phase II study of adoptive immuno- Macrophage plasticity, polarization, and function in health and disease. therapy using dendritic cells pulsed with tumor lysate in patients with J Cell Physiol. 2018;233:6425–40. hepatocellular carcinoma. Hepatology. 2009;49:124–32. 127. Najafi M, Hashemi Goradel N, Farhood B, Salehi E, Nashtaei MS, 148. Zhang B, Yin Y, Lai RC, Lim SK. Immunotherapeutic potential of extracel- Khanlarkhani N, Khezri Z, Majidpoor J, Abouzaripour M, Habibi M. Mac- lular vesicles. Front Immunol. 2014;5:518. rophage polarity in cancer: a review. J Cell Biochem. 2019;120:2756–65. 149. Mbongue JC, Nieves HA, Torrez TW, Langridge WH. The role of dendritic 128. Hu C, Lei T, Wang Y, Cao J, Yang X, Qin L, Liu R, Zhou Y, Tong F, Ume- cell maturation in the induction of insulin-dependent diabetes mellitus. shappa CS. Phagocyte-membrane-coated and laser-responsive nano- Front Immunol. 2017;8:327. particles control primary and metastatic cancer by inducing anti-tumor 150. Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immu- immunity. Biomaterials. 2020;255:120159. nol. 2016;37:855–65. 129. Gay LJ, Felding-Habermann B. Contribution of platelets to tumour 151. Cheng S, Xu C, Jin Y, Li Y, Zhong C, Ma J, Yang J, Zhang N, Li Y, Wang C. metastasis. Nat Rev Cancer. 2011;11:123–34. Artificial mini dendritic cells boost T cell-based immunotherapy for 130. De Witt SM, Swieringa F, Cavill R, Lamers MM, Van Kruchten R, Masten- ovarian cancer. Adv Sci. 2020;7:1903301. broek T, Baaten C, Coort S, Pugh N, Schulz A. Identification of platelet 152. Zhang C, Zhang J, Shi G, Song H, Shi S, Zhang X, Huang P, Wang Z, function defects by multi-parameter assessment of thrombus forma- Wang W, Wang C. A light responsive nanoparticle-based delivery tion. Nat Commun. 2014;5:1–13. system using pheophorbide a graft polyethylenimine for dendritic cell- 131. Nelson VS, Jolink A-TC, Amini SN, Zwaginga JJ, Netelenbos T, Semple based cancer immunotherapy. Mol Pharm. 2017;14:1760–70. JW, Porcelijn L, de Haas M, Schipperus MR, Kapur R. Platelets in ITP: 153. Fang RH, Jiang Y, Fang JC, Zhang L. Cell membrane-derived nanomate- victims in charge of their own fate? Cells. 2021;10:3235. rials for biomedical applications. Biomaterials. 2017;128:69–83. 132. Chen S, Lv M, Fang S, Ye W, Gao Y, Xu Y. Poly (I: C) enhanced anti-cervical 154. Sun Q, Wu J, Jin L, Hong L, Wang F, Mao Z, Wu M. Cancer cell cancer immunities induced by dendritic cells-derived exosomes. Int J membrane-coated gold nanorods for photothermal therapy and radio- Biol Macromol. 2018;113:1182–7. therapy on oral squamous cancer. J Mater Chem B. 2020;8:7253–63. 133. Shang Y, Wang Q, Wu B, Zhao Q, Li J, Huang X, Chen W, Gui R. Platelet- 155. Rao L, Bu LL, Meng QF, Cai B, Deng WW, Li A, Li K, Guo SS, Zhang WF, membrane-camouflaged black phosphorus quantum dots enhance Liu W. Antitumor platelet-mimicking magnetic nanoparticles. Adv Func anticancer effect mediated by apoptosis and autophagy. ACS Appl Mater. 2017;27:1604774. Mater Interfaces. 2019;11:28254–66. 156. Wu H-H, Zhou Y, Tabata Y, Gao J-Q. Mesenchymal stem cell-based 134. Wu H, Mu X, Liu L, Wu H, Hu X, Chen L, Liu J, Mu Y, Yuan F, Liu W. Bone drug delivery strategy: from cells to biomimetic. J Contr Rel. marrow mesenchymal stem cells-derived exosomal microRNA-193a 2019;294:102–13. reduces cisplatin resistance of non-small cell lung cancer cells via 157. He H, Guo C, Wang J, Korzun WJ, Wang X-Y, Ghosh S, Yang H. Leutu- targeting LRRC1. Cell Death Dis. 2020;11:1–14. some: a biomimetic nanoplatform integrating plasma membrane 135. Nath S, Mukherjee P. MUC1: a multifaceted oncoprotein with a key role components of leukocytes and tumor cells for remarkably enhanced in cancer progression. Trends Mol Med. 2014;20:332–42. solid tumor homing. Nano Lett. 2018;18:6164–74. 136. Gordon-Alonso M, Hirsch T, Wildmann C, van der Bruggen P. Galectin-3 158. Sun M, Duan Y, Ma Y, Zhang Q. Cancer cell-erythrocyte hybrid captures interferon-gamma in the tumor matrix reducing chemokine membrane coated gold nanocages for near infrared light-activated L ei et al. Journal of Nanobiotechnology (2022) 20:45 Page 21 of 21 photothermal/radio/chemotherapy of breast cancer. Int J Nanomed. 2020;15:6749. 159. Gong C, Yu X, You B, Wu Y, Wang R, Han L, Wang Y, Gao S, Yuan Y. Macrophage-cancer hybrid membrane-coated nanoparticles for targeting lung metastasis in breast cancer therapy. J Nanobiotechnol. 2020;18:1–17. 160. Li M, Xu Z, Zhang L, Cui M, Zhu M, Guo Y, Sun R, Han J, Song E, He Y, Su Y. Targeted noninvasive treatment of choroidal neovascularization by hybrid cell-membrane-cloaked biomimetic nanoparticles. ACS Nano. 2021;15:9808–19. 161. Giampietro C, Taddei A, Corada M, Sarra-Ferraris GM, Alcalay M, Caval- laro U, Orsenigo F, Lampugnani MG, Dejana E. Overlapping and diver- gent signaling pathways of N-cadherin and VE-cadherin in endothelial cells. Blood J Am Soc Hematol. 2012;119:2159–70. 162. Pisano S, Pierini I, Gu J, Gazze A, Francis LW, Gonzalez D, Conlan RS, Corradetti B. Immune (Cell) derived exosome mimetics (IDEM) as a treatment for ovarian cancer. Front Cell Dev Biol. 2020;8:553576. 163. Susa F, Limongi T, Dumontel B, Vighetto V, Cauda V. Engineered extracellular vesicles as a reliable tool in cancer nanomedicine. Cancers. 1979;2019:11. 164. Jin K, Luo Z, Zhang B, Pang Z. Biomimetic nanoparticles for inflamma- tion targeting. Acta Pharmaceut Sin B. 2018;8:23–33. 165. Xia Y, Rao L, Yao H, Wang Z, Ning P, Chen X. Engineering mac- rophages for cancer immunotherapy and drug delivery. Adv Mater. 2020;32:2002054. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

Journal

Journal of NanobiotechnologySpringer Journals

Published: Jan 21, 2022

Keywords: Nanocarriers; Cell membrane; Cancer; Chemotherapy; Targeted drug delivery

There are no references for this article.