Abstract
Background
Inspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells.
Key scientific concepts of review
Nanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems.
Aim of review
This review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects.
Graphical Abstract
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Background
Cancer has been a worldwide concern for a long period of time and is the second largest cause of mortality [1]. Conventional chemotherapy, as one of the most frequently used methods for cancer treatment, remains unsatisfactory owing to the significant side effects and the poor targeting ability of anti-cancer drugs [2]. To overcome these issues, significant research and development has been conducted on targeted drug delivery systems (TDDS), particularly nanocarrier-based TDDS [3]. The benefits of nanocarriers, which include the ability to be modified, a large capacity for drug loading, and tunable physiochemical characteristics, make them ideal for encapsulating anti-cancer drugs and altering their stability, solubility, and in vivo behaviour [4]. Nevertheless, surface modification of nanocarriers may enhance their blood circulation and enable more precise targeting, thus increasing effectiveness while trying to minimize side effects [5]. However, there are also many disadvantages that make it difficult for nanocarriers to live up to clinical standards. The immune system recognizes and eliminates the majority of nanocarriers as foreign substances. Since the polyethylene glycol (PEG), a hydrophilic polymer, was initially incorporated into a protein medication [6], PEGylation has been the most frequently utilized modification technique in drug delivery applications [7]. Additionally, the targeted capacity of nanocarriers was highly reliant on the surface modification, which was challenging to manufacture and accomplish [8]. As a result, TDDS delivered through nanoparticles has not yet achieved its full therapeutic potential.
The drug-delivery system's (DDSs) technology continues to advance, making it possible to administer more potent drugs [9]. Drug research efforts are significantly aided by therapeutic compounds’ capacity to remain intact in a hostile extracellular milieu [10]. In this connection, efforts to reduce immunogenicity and improve biopharmaceutical stability through modification of biopharmaceuticals have increased [11]. Cells in the early 1980s were used as drug delivery vehicles, which substantially increased the drugs' retention and targeting capabilities [12]. Despite the increasing use of live cell-based carriers, several shortcomings persist. One major concern is passenger drug activity, as drugs may be digested by the cell carrier’s lysosomes [13]. Moreover, drug release is difficult to control due to exocytosis or leakage during transport [14]. Faced with these challenges, scientists recently discovered a natural way to design biomimetic cell membrane nanocarriers. At first, the biomimetic cell membrane nanocarriers were made from a poly (lactic-co-glycolic acid) (PLGA) core and a red blood cell (RBC) membrane shell, using a co-extrusion process [15]. Then, different cell membrane-coated nanocarriers (CMCNs) were explored with different nanocarrier cores and membrane materials. The incorporation of nanocarriers into the cell membrane merges the advantages of material science and biomimicry. It is important to note that CMCNs can be portrayed as autogenous cells to prolong blood circulation time and avoid immune system elimination, both of which are required for the enhanced permeability and retention (EPR) effect of cancer targeted chemotherapy [16] (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
Moreover, different cell membranes may confer different functions on CMCNs, resulting in varying in vivo behaviour. Biomimetic technology, a relatively new procedure, satisfies these requirements and is currently being used in designing drug nanocarriers [17, 18]. By drawing inspiration from nature that comprises biological elements and living matter, this technology aims to overcome the shortcomings of current drug delivery systems. An ideal biomimetic delivery system exploits pathogens’ immune evasion and intracellular uptake tactics. However, delivery systems derived from pathogens continue to raise safety concerns, including immunogenicity and virulence [19].
Advantages of CMCNs based drug delivery systems
CMCNs have notably contributed to suppressing drug resistance in the use of nanocarriers for cancer therapies. Biomimetic CMCNs possess special characteristics, such as prolonged drug delivery, immunological evasion, homotypic targeting, longer blood circulation, and specific ligand/receptor recognition. To get beyond the restrictions of cell toxicity, differentiation, and sensitivity in cell-based delivery systems, CMCNs utilize therapeutically relevant cell membrane proteins as an alternative to the whole cell. Because a longer circulation time benefits with the potential of sustained drug delivery and increases the probability of sustained distribution into the circulation [20]. The biomimetic CMCNs provide bio-modulation and more control in this regard. The CMCNs prepared by coating RBC membrane on PLGA nanocarriers improved the nanocarriers’ retention in the blood by 72 hours, compared to 15.8 hours for typical synthetic stealth nanocarriers [15]. Moreover, PLGA nanocarriers with a fluorocarbon core masked in an RBC membrane were used for delivering oxygen to solid tumours, demonstrating another application of CMCNs delivery to improve blood circulation time via the EPR approach [21].
The reduced immunogenic characteristics of cancer cell membranes and their homing abilities improve targeted drug delivery at the cancer site. In this respect, Cao et al. investigated the interaction between VCAM-1 of metastatic cancer cells with macrophage α4 proteins to transport cytotoxic anticancer drugs to the lungs [22]. Using the adhesion characteristics of galectin-3 and T antigen in cancer cell membranes, Fang et al. demonstrated homotypic tumour targeting [23]. Furthermore, when compared to other active targeting methods, incorporating iron oxide nanocarriers into fractured cancer cell membranes for tumor targeting demonstrated superior homing to homologous tumors in vivo [24]. Recently designed leuko-like vectors (LLV) targeting metastatic niches utilizing neutrophil membrane-coated nanocarriers have shown a two- to threefold increase in metastatic foci accumulation compared to PLGA-PEG nanocarriers and bare nanocarriers, respectively [25]. This affinity for metastatic niches is enhanced by the presence of N cadherin, Mac-1, and other sticky proteins produced on neutrophil membranes on CMCNs, as opposed to the usual PEG coating employed to prolong circulation half-life and prevent clearance [26]. Interestingly, PLGA nanocarriers coated with T lymphocyte membranes were also capable of retaining their lymphocyte coating and evading lysosome sequestration, while bare nanocarriers were caught in endolysosomal compartments prone to breakdown in in vivo [27]. Moreover, this study also discovered that T lymphocyte-coated nanocarriers had a twofold increase in particle density throughout tumours in mice when compared to naked nanocarriers. Numerous additional research groups are attempting to harness the cell membrane’s inherent properties to create biomimetic drug carriers for cancer treatments.
Considerations of CMCNs
Choice of cell membrane
A thorough understanding of the homeostasis, function, and structure of cells in their complex physiological context provides key hints for better biointerfacing of synthetic DDSs [28]. A delivery system with the ability to protect cargo and carry cell features like autonomous activity, compartmentalization, flexibility, and form can be more convenient and beneficial than other delivery systems. The cell membrane repeats the surface functionality of cells and extracellular vesicles as it is the fundamental structural component of them. It is primarily made up of carbohydrates, proteins, and lipids, and it interacts with the environment to survive and grow [29]. Carbohydrates play a part in cellular recognition, whereas proteins are responsible for adhesion and signaling, and lipid bilayer formation combines structural fluidity and stiffness [30,31,32]. Cell membranes can be differentiated based on the properties and composition of these three components in them. The potential to profit from native cell membrane functions has sparked tremendous scientific interest in coating nanocarriers. If done appropriately, the cell membrane retains its capability, and its coating enhances biointerfacing.
The selection of the appropriate cell type or cell membrane is crucial for ensuring site-specific distribution and targeting as well as for minimizing adverse interactions with complementing systems in vivo. Every cell type has unique biological features, making them suitable for certain therapeutic applications such as infectious diseases, inflammatory diseases, cancer, and personalized therapy [33]. For example, the membrane of RBCs is rich with glycophorins that play a key role in attracting pathogens to their surface and killing them via oxytosis [32]. The application of an RBC membrane to the nanocarriers thereby increases pathogen clearance, long-term circulation, and cell viability. Platelets interact with injured endothelial cells and engage with immune cells to mobilize them toward the inflamed site [34]. As a result, covering the nanocarriers with the platelet membranes allows for selective adherence to tumour tissues or wounded vessels, targeting circulatory tumour cells, pathogen eradication, and the capability to elude detection by macrophages. Similarly, macrophage membranes like other leukocytes carry adhesion molecules like VLA-4, LFA-1, PSGL-1, L-selectin, and P-selectin that help with cell adherence [35]. Thus, coating the nanocarrier with macrophage membrane has the ability to bind pathogens while avoiding macrophage recognition and offering active targeting at the cancer site. Moreover, tumor-specific adhesion molecules and antigens such as mucoprotein-1, epithelial-adhesion molecules, lymphocyte-homing receptors (like CD44), galectin-3, integrins, and cadherins are overexpressed on the surface of cancer cell membranes [36]. These antigens and adhesion molecules play a critical role in the contacts among cells and between cells and the surrounding tissue matrix. Generally, cancer cell membranes can cling to their homologous cells [37]. So, wrap** a nanocarrier with a cancer cell membrane prevents macrophage detection, allowing for homotypic tumour targeting, and contributes to the design of personalized cancer therapy.
Cell source
In order to use maximum cell membrane properties, it is essential to consider the state, form, and source of the cell. In this connection, Evangelopoulos et al. demonstrated that the cell source determines the immunogenicity of biomimetic nanocarriers [38]. They studied multilayer cell membrane generated vesicles from various sources for phagocytosis, opsonization, and targeting of inflamed regions. Literature showed that the use of a syngeneic cell membrane coating increased the avoidance of absorption by the liver and immunological repertoire cells [38]. To isolate the cell membrane for the coating of nanocarriers, it is preferred to choose homotypic cells in a healthy state and nourishing phase. The real therapeutic effectiveness of CMCNs requires homogeneity of the cell population. To fulfil this requirement, quantification or expression levels of specific surface markers (e.g., receptors or ligands) plays a dominant role. For this purpose, flow cytometry, Blot Western, and SDS-PAGE techniques can be used to evaluate the cellular state and homogeneity of cell membranes [39]. Identification of cell biomarkers and other ligands for signal transduction, targeting, or any other approach would enhance translational effects.
Membrane stability
CMCNs are preferred for use over targeting nanocarriers prepared via a bottom-up approach because they possess numerous characteristics, including signal transduction, immune evasion, targeting, and therapeutic advantages. To maximize the therapeutic potential of CMCNs, the structural and functional characteristics of the cell membrane should be preserved prior to coating drug carriers. The cell membrane’s stability is critical in determining the overall durability of CMCNs. The microenvironment of tissue and circulation naturally creates torque and shear forces on cells and nanocarriers. Cells survive with these forces and respond to them by actively modulating their cytoskeleton-membrane interactions, lipid profile, ligand density, and ligand concentration. For example, the interaction of intracellular proteins with the cell membrane strengthens the reliability of natural cells. During the isolation of the membrane, some key stability regulators of the cell membrane may be lost or changed. As a result, determining the overall membrane stability of CMCNs becomes critical before moving further with biomimetic-based treatment [40]. Numerous techniques for determining the stability of membrane structures are described in the literature. For visualizing the structural integrity and morphology of cell membranes, advanced fluorescence, lipophilic dye enhanced, Cryo-TEM, and spectrophotometric techniques, for example, are all extremely useful [41]. When it comes to the mechanical or elastic integrity of membranes, ektacytometry may be the best tool for determining membrane elongation in dynamic shear stress [42]. Additionally, the source of lipid composition in the cell also influences the overall stability of CMCNs. In one study comparing the lipidomic profiles of cells, a higher proportion of unsaturated phospholipids was observed in primary cell cultures than other cultured. X-ray scattering, FTIR, and colorimetric lipid assays are all useful tools for assessing the qualitative composition of phospholipids [43].
Membrane-related proteins
The CMCNs interact with the local environment of tissues and cells through proteins present on the cell membranes. So, the appropriate membrane proteins must be kept up in the cell culture. Several transfection and chemical signaling methods may be used to regulate protein expression and cellular states in culture. In fact, long-term cell growth of some cell types may alter their desirable characteristics for CMCNs applications. For example, the culture condition affects the phenotypes of mesenchymal stem cells, which vary across individuals, cell groups, and even batches. The expansion of mesenchymal stem cells in in vitro not only alters mRNA expression patterns but also affects the surface proteins involved in migration and adhesion (e.g., C-met/HGF, CXCR7, CXCR4, etc.) [44]. In the case of nanocarriers coated with immune cell membrane, it is essential to consider the state and cellular source of immune cells, since they undergo different modifications throughout the pro- and post-inflammatory phases (e.g., pro- and post-inflammatory macrophages M1 and M2).
While obtaining the desired membranes is still an attractive approach, it is becoming increasingly favorable to modify the cell surface using proteins, peptides, or small molecules before harvesting the membranes [45]. In this scenario, cell membrane receptors are becoming less sensitive, and this is unknown at this time. In the case of highly biotinylated membranes of erythrocytes, they are more likely to be taken up by macrophages because of the presence of C3b proteins on them. It is suggested that biotinylation may also disable complement regulators or self-markers on the cell surface [46]. As CMCNs appear to have no significant effect on cellular behaviours, they do not entirely reflect what the cells naturally do. Stephan et al. performed a detailed investigation of nanocarriers-tethered T cells to monitor synapse formation, transmigration, antigen, and cell division. They found that the ability of the cell to perform physiological functions was not affected by the conjugation of nanocarriers to the cell membrane [40]. The degree of immune response variability is proportional to the variety of different sources employed in cell membrane engineering and to the technology used to design the membranes. To successfully apply biomimetic-based drug delivery applications to the clinic, it is essential to have extensive CMCNPs characterization and qualification.
Cell membrane extraction
In order to successfully isolate the cell membrane, cell membrane extraction protocols must ensure that there is minimal or no cytosol, mitochondrial, or nuclear contamination. Making use of a pure cell membrane improves surface coating efficiency and uniformity, allowing for maximum functional and structural replication on the nanocarrier surface. To preserve membrane proteins from degeneration, the extraction medium is supplemented with phosphatase/protease inhibitor cocktails that are stored at ice-cold temperatures. Prior to extraction, cells are thoroughly cleaned with saline buffer to remove any remaining remnants of the cell culture medium.
Some cells lack nuclei (e.g., RBCs and platelets), making membrane extraction easy. During membrane extraction, cells are separated first from their tissues using the most suitable techniques. For RBCs, a hypotonic treatment certainly disintegrates the cells and frees the cell membrane to collect through centrifugation in the form of a pink RBC pallet [47]. Again and again, centrifugation purifies the pallet from haemoglobin impurities. For platelets, it is recommended to do multiple freeze–thaw sequences to rapture their membrane by breaking ice crystals to release the cytosol [48]. The free cell membrane is then collected through centrifugation. Sometimes, the collected platelet membranes are treated with a discontinuous sucrose gradient to purify the platelet membrane from any high-density granules, proteins, and intact platelets.
Extraction of the membrane from nucleus-containing cells is slightly more difficult than from nucleus-free cells. Nucleus-containing cells include β-cells, fibroblasts, cancer stem cells, and immune cells (e.g., T cells, NK cells, neutrophils, monocytes/macrophages). These cells can be isolated from established cell lines like MCF-7, 4T1, J447, NK-92, etc., or from blood or tissues (stem cells, cancer cells, T cells, neutrophils, NK cells, etc.). By combining hypotonic treatment with physical disruption procedures, it produces an extract that contains high-density granules, intact cells, and free cell membranes. Finally, the cell membrane is isolated from the mixture through the use of discontinuous sucrose gradient ultrafiltration or differential centrifugation [49, 50].
Membrane functional components such as cholesterol (making structural components), carbohydrates (cellular recognition components), and transmembrane proteins (adhesion and signaling components) can be lost during membrane isolation. Cholesterol helps keep the cell membrane rigid. This loss may reduce the membrane’s mechanical stability. Moreover, proteins also act as membrane skeleton stabilizers by selectively attaching to the junction complex as well as other membrane proteins such as tropomyosin [51]. Therefore, hypotonic buffers containing divalent ions (such as MgCl2) or even adding cholesterol can be effective in reducing protein loss while maintaining membrane stability [52]. Moreover, the right pH, soft rapturing procedures, proper ice-cold conditions, and mild lysis buffer must be adopted for membrane extraction to avoid denaturation of transmembrane proteins/receptors. Once the cell membrane has been isolated, it is freeze dried and kept at − 80 °C to ensure that membrane proteins retain their long-term consistency and features.
Choice of template
A template is a structural component of the CMCNs which can be used for diagnosis and drug delivery due to its various desirable features. Templates can be classified as organic and inorganic, where liposomes, gelatin, and PLGA are organic templates, while inorganic templates include iron oxide (Fe3O4), gold, mesoporous silica, upconversion nanoparticles (UCNPs), PLNPs, and MOFs. Organic templates are simple to use and provide benefits, including biocompatibility, biodegradability, and nontoxicity [53]. Inorganic templates, on the other hand, have electrical, optical, and magnetic properties that influence their selection in a CMCN [54].
For clinical translation, template biodegradability and biocompatibility are critical which are influenced by the degradation and byproducts formation and their subsequent interactions with human body. 231,231 Renal clearance helps avoid the templates adverse effects [55]. FDA-approved templates are regarded the safest in terms of toxicities. Because most organic templates are safer than inorganic ones, they have been practiced in clinical trials [56]. In 2011, a PLGA nanoparticle was used as a template to build these imitating systems [15]. As a synthetic polymer, PLGA can be fabricated into nano and microparticles and have been commonly used for RBC, platelets, cancer cells, neutrophils, dendritic cells, macrophages, cardiac stem cells, and various other templates [47, 49, 57,58,59,60]. Gelatin, a natural polypeptide widely used in medicines, food, and cosmetics, has also been utilized for assembly of CMCNs. Patient-derived tumour cells, T-cell, stem cell, and RBC are employed to coat gelatin templates for CMCNs [61,62,63,82]. Gold particles can be shaped into nanoparticles, nanoshells, nanorods, and nanocages, which are all used to fabricate CMCNs.
Procedures for engineering CMCNs
Preparation of CMCNs
The preparation of CMCNs can be processed through four major steps. The first step is to separate the membranes from the parent cells by using a hypotonic buffer to lysate them. Second, the purification of the mixture to separate cellular components and cell membranes by centrifugation [83]. The centrifugation process will be different depending on the cell type. For example, irregular sucrose gradient centrifugation is needed to prepare eukaryote cell membranes because this treatment separates the membrane from nuclei and other cell components. Whereas nuclei-free membranes like RBCs do not require this treatment. Third, preparation of the inner core. Liposomes, gelatin, PLGA, poly (-caprolactone), iron oxide nanoparticles, gold nanoparticles, mesoporous silica nano-capsules, silicon nanoparticles, and other synthetic materials make up the inner cores. The inner core selection for CMCNs is based on the types of cargo to be transported (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
To prepare CMCNs, the inner core nanoparticles and the cell membranes are fused together. The fusion process must be carried out in such a way that it should not result in protein denaturation or drug leakage. The two most frequently used procedures for the fusion of the inner core into cell membranes are ultrasonic treatment and membrane extrusion [84, 109,110,111]. However, RBC membrane can also be functionalized with iRGD peptide and folate receptor to target breast cancer [112, 113]. For targeting the brain, targeting ligands such as T7, cRGD peptide, DCDX peptide, and NGR peptide are incorporated into the RBC membrane [22, 35, 127]. The microenvironment of cancer affects macrophages, so their antitumor effect is often enhanced by administrating macrophages with other therapies. Hu et al. synthesized biomimetic nanocarriers [(C/I)BP@B-A(D)&M1m] that were encapsulated in the M1 macrophage membrane [128]. Numerous molecules involved in over expression of major histocompatibility complex (MHC) and costimulatory signal transduction on the cell membrane enabled (C/I)BP@B-A(D)&M1m to target cancer tissues effectively. When combined with laser irradiation, (C/I)BP@B-A(D)&M1m efficiently released drugs at the site of application. Liu et al. synthesized a mixed micelle containing bilirubin (ROX-responsive) and chlorin e6 (photosensitizer), loaded with paclitaxel dimer, and wrapped into a macrophage membrane. By co-delivering paclitaxel dimer and Ce6, these nanocarriers effectively combine photodynamic and chemotherapy therapy. Macrophage membranes can shield drugs from being taken up by macrophages, which increases the likelihood of nanocarriers being absorbed and retained by tumor cells.
Platelet
Platelets are nucleate cells of blood produced by megakaryocyte fragmentation and are involved in tumor metastasis, thrombosis, and blood coagulation [129]. Platelet membranes have the ability to escape phagocytosis in systemic circulation. Like RBCs, the platelet membrane has CD47 receptors. CD47 receptors interact with regulatory proteins that inhibit macrophage receptors and can affect the pharmacokinetics of encapsulated drugs. Platelet glycoproteins may also interact with collagen-rich plaque [130], assisting in the targeting of atherosclerotic sites by platelet membrane-coated nanocarriers. So, platelet membrane coating enables nanocarriers to escape from macrophages and selectively bind injured vessels and tumour tissues. Because of these properties, platelet membrane coated nanocarriers can be used to target breast cancer lung metastasis and circulating tumour cells [57, 75]. When using nanocarriers coated with platelet membranes, it is suggested to focus on CD47 receptor integrity. A functional change in the CD47 receptor may affect biodistribution and pharmacokinetics of nanocarriers. Nanocarriers coated with platelet membranes should not be used in patients with autoimmune diseases. Platelet autoantibodies may form immune complexes with nanocarriers [131].
In recent years, the number of platelet membrane coated drug delivery systems has increased rapidly due to their easy extraction, purification, and accumulation at cancer sites [132]. Rong et al. reported a nanocarrier of platelet membrane coated black phosphorus quantum dots carrying hederagenin (PLT@BPQDsHED) [133]. PLT@BPQDs-HED had a stronger fluorescence signal at the cancer site and a higher retention rate than the control group after 48 h. A higher efficiency of drug delivery is achieved by PLT@BPQDs-HED because selectin on the platelet membrane specifically attaches to the CD44 receptor overexpressed in cancer tissue. Platelets are much more related to cancer cells, and the nanocarriers that are wrapped into platelet membranes avoid clearance by the immune system and specifically target cancer tissue via the proteins on the membrane surface. Platelet membrane-coated drug delivery systems have the potential to be used in combination with immunotherapy and phototherapy. Wu et al. wrapped nanocarriers comprising the anticancer drug and polypyrrole into platelet membranes [134]. Platelet membrane enables the drug delivery system to escape from immune systems and target the cancer tissue, laser irradiation triggers polypyrrole to cause hyperthermia and ablate the cancer cells, and anticancer drugs are also discharged from the nanocarriers to destroy the cancer tissue.
Cancer cell
Cancer is described as abnormal cell growth that could lead to metastasis. Cancerous cells’ membrane display a variety of tumour-specific adhesion and antigen moieties. There are a wide range of molecules involved in cell–cell and cell–matrix adhesion, such as mucoprotein-1, epithelial adhesion moieties, lymphocyte-homing receptors, galectin-3, integrins, and cadherins [36, 135, 136]. Cancer cells possess properties that collectively serve a self-protective function, such as homotypic cell adhesion and immune system evasion [137]. Since these cells have unique characteristics, their membranes have gained popularity as coating stuff for nanocarriers. The dispersed membrane of cancer cells on nanocarriers allows various characteristics of cancer cells to be introduced to the nanocarriers for targeting homotypic tumours and develo** personalized cancer therapy [161]. The substantial fluorescence colocalization of angiogenic retinal endotheliocyte membranes and HMCNs in the tube formation experiment also indicated the nanocarriers’ targeting ability. Furthermore, using a quantitative examination of the mean fluorescence intensity, the group treated with HMCNs drastically decreased damage area and choroidal neovascularization leakage in contrast to the group treated with pure CMCNs in a choroidal neovascularization mouse model induced by laser. In conclusion, dual-fused membrane-based nanocarriers offer significant advantages over currently available invasive therapies.
Challenges and future directions
Numerous advantages have been reported for CMCNs, particularly in terms of biocompatibility and targeting. Synthetic DDSs currently available are basically foreign substances with the potential for immunogenicity and toxicity. Whereas cell membranes are endogenous, they are considered biocompatible and perform a variety of biological functions like the source cell. However, certain issues must be resolved before these carriers can continue to evolve and move from the laboratory to the clinic.
The first and most important question to be addressed is about the yield of cell membranes and extracellular vesicles. Not only do existing separation technologies produce a negligible amount of cell membranes and extracellular vesicles, but they are also prohibitively expensive for large-scale production. As a result, more sophisticated large-scale manufacturing methods are required to continue expanding the application of cell membrane. In recent years, to address the yield issue, extensive work has been carried out on techniques which are used for generating artificial vesicles when the membrane is ruptured via extrusion. For example, the same number of THP-1 cells yield more than twice as many simulated exosomes as natural exosomes, and the drug encapsulating and releasing rates of the simulated exosomes are also higher [162]. The extraction and purification procedures must also be revised and optimized, as many cells must still be cultured to obtain an adequate number of membranes, and the preparation procedure must still be simplified [118]. For RBCs membrane-coated nanocarriers that lack a targeting ability, the membranes must be modified to reach the target site for therapeutic cargo release, but this will likely change the membrane’s original structure and reduce its biocompatibility. Platelet membranes are highly sensitive, so finding an appropriate loading scheme to ensure adequate drug loading and reliable delivery to the target tissue is challenging. The toxicity and stability of modified membranes must also be studied, especially as nanocarriers for cancer therapy. To achieve the desired dose and release profile, the drug loading method should be chosen carefully [163].
Moreover, a complete understanding of the mechanism of transporting cell membranes extracted from different sources in vivo is unknown and requires further research. For example, therapeutic molecules delivered by white cell membrane carriers may activate immune system components and cause inflammation [164]. When cancer cell membrane is used, it may cause cancer in the body if the parent cancer cells’ genetic material is not completely removed. Procedures for purifying and characterizing cell membranes are not consistent and differ from laboratory to laboratory, causing confusion about the physicochemical features of the cell membrane. So, it is necessary to share the scientific data and develop a standardized procedure for cell membrane quality control that is highly repeatable. Nanocarriers wrapped into cell membranes and extracellular vesicles can target cancer tissues crossing biological barriers. Some cells can be used to both extract membranes and isolate extracellular vesicles to transport drugs. While it is relatively simple to extract and prepare the cell membrane, the targeting ability may be compromised due to protein loss during membrane extraction. However, extracellular vesicles are difficult to prepare, they generally retain all membrane components, giving them excellent targeting ability [165]. As a result, the appropriate carrier must be chosen according to the experiment’s objective in order to maximize the therapeutic effect.
Conclusions
The development of therapeutics derived from cell membrane material is a rapidly growing field of research that is particularly appealing because it involves an organic cellular networking system. Biomimetic technology has the advantage of taking advantage of the natural mechanisms of living matter, but it is also a double-edged sword. It is difficult to know which components, out of the multiple factors, confer membrane functionality, and so the ratio of each component needs to be modified as needed. To develop drug-containing membrane-coated carriers, a similarly and standardized manufacturing process will be required. Despite the difficulties associated with processing variables, manufacturing, and quality control, vesicles derived from natural cells have the advantage of being bioactive, reflecting the features of the parent cells. Although membrane-coated nanocarriers face numerous challenges, a powerful advantage of ‘mimicking nature’ overrides many disadvantages of traditional DDSs and offers a more efficient approach for cancer treatment. With the rapid advancement of nanotechnology, proteomics, bioinformatics, pharmacology, and material science, it is expected that the combination of DDSs and cells will overcome numerous obstacles, revolutionize current medical technology, and open up new avenues for targeted cancer therapy.
Availability of data and materials
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Authors are grateful to Hospital of Hangzhou Medical College for providing necessary facilities.
Funding
This study was supported by the Foundation of Science Technology Department of Zhejiang Province (No. LGF22H080012, LY19H160037, LGF18H160025) and the funds from Zhejiang Medical Technology Plan Project (No. 2020KY052).
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WL, CY, YW, GR, XH, XT, and SW wrote different sections of the manuscript. WL, CY, and SW edited the manuscript. All authors read and approved the final manuscript.
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Lei, W., Yang, C., Wu, Y. et al. Nanocarriers surface engineered with cell membranes for cancer targeted chemotherapy. J Nanobiotechnol 20, 45 (2022). https://doi.org/10.1186/s12951-022-01251-w
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DOI: https://doi.org/10.1186/s12951-022-01251-w