Biomimetic nanosystems based on cell membranes (BNCMs) for cancer immunotherapy

Abstract

With the development of nanosystems, they are gradually utilized to ameliorate diverse cancer therapies. Specifically for immunotherapy, most nanosystems are elaborately designed to initiate the self‐sustaining “cancer immunity cycle (CIC)” to elicit the immune response. However, owing to the highly complex circulatory environment, nanosystems may face issues like nonspecific nanoparticle uptake and rapid clearance, leaving enormous room for advancement. For employing the biomimetic design in nanosystems, biomimetic nanosystems based on cell membranes (BNCMs) inherit various functional molecules from source cells, permitting precise tumor targeting, enhancing blood circulation, and conferring more desired functionality for a more robust immune response. To take full advantage of the BNCMs, understanding their functions in cancer immunotherapy is essential. In this review, the unique properties of BNCMs derived from various cells and main preparation strategies are introduced. Subsequently, the recent advances of BNCMs for improving cancer immunotherapy are discussed from the aspects of their roles in particular stages of the CIC, and the working mechanisms of the outer cell membranes are highlighted. Finally, along with the analysis of existing bottlenecks for clinical translation, some suggestions for the future development of BNCMs are put forward.

INTRODUCTION

Immunotherapy, which mostly acts by initiating or reinitiating the self-sustaining “cancer immunity cycle” to elicit the immune response and eradicate tumors,¹ has gathered substantial attention according to the notable clinical achievements of immune-checkpoint inhibitors (ICIs)^2–4 and chimeric antigen receptor (CAR) T cell therapy.^5–7 Immunotherapy possesses numerous advantages over other conventional cancer treatments, including surgery, chemotherapy, and radiotherapy. To be specific, immunotherapy can eradicate local and metastatic tumors, while most cancer therapies are only effective in the treatment of primary tumors. Furthermore, immunotherapy fosters a durable immune memory that acts as a potent shield, mediating immune protection and thereby thwarting the recurrence of tumors.^8–10 Despite cancer immunotherapy improves survival and quality of life for patients, there are still several barriers to the wide application of immunotherapy. For instance, the main shortcoming of ICIs is the failure to provoke an effective immune response in certain types of tumors, presumably owing to their lower immunogenicity.^11,12 Meanwhile, since the action mechanism of ICIs depends on the inhibition of physiological brakes on immune activation, their off-targeting leads to immune-mediated inflammation in multiple organs or tissues.^13–16 Consequently, there is an urgent necessity for a delivery method that can potentiate the immune response while simultaneously mitigating adverse effects.

Nanosystems that feature better delivery efficacy and increased safety are promising option.¹⁷ However, owing to the highly complex components in the blood and various biological obstacles, conventional nanosystems may face issues of nonspecific nanoparticle uptake and rapid clearance. In this circumstance, surface engineering of nanosystems is proposed to prolong blood circulation while promoting specific targeting, thereby reducing harm to healthy tissues and systemic toxicity.^18–20 Generally, common modification strategies mainly consist of polyethylene glycols (PEGs) and ligands with targeted functions, such as antibodies, small molecules, and peptides. Recently, however, an expanding evidence base has emerged, suggesting that PEGylated products have the potential to induce immunogenicity^21,22 and, consequently, trigger the accelerated blood clearance phenomenon in nanosystems.²³ Moreover, this modification strategy encounters difficulties in replicating the intricate, collective functionality of biological systems, necessitating substantial investments of time and resources for manufacturing purposes.

Based on the above issues, the concept of “biomimetic” is being harnessed to refine nanosystems. Biomimetic, in this context, refers to the extraction, isolation, and purification of endogenous substances directly from organisms, or the synthesis of components that mirror the structure and function of these natural substances, thereby offering a more biologically compatible approach.²⁴ The ultimate purpose of them is to imitate the function of biological structure in living organisms as closely as possible. To date, there are mainly three strategies for fusing biomimetic design principles with nanoparticles: first, using endogenous substances to modify the surface of nanoparticles, mainly including small molecules, carbohydrates, and targeting peptides²⁵; second, utilizing endogenous components or their analogs as the drug carrier, such as albumin, lactoferrin, and lipoproteins^26–30; third, coating nanosystems with the cell membrane. Among all of them, biomimetic designs based on cell membranes have provided a simplified and straightforward approach to replicate the biological interface and thus develop biomimetic nanosystems with ideal properties. This promising type of nanosystem is typically crafted by encasing synthetic cores within a layer of diverse cell membranes, resulting in a core-shell nanostructure that mimics cellular properties. This innovative approach has demonstrated substantial potential for various biomedical applications.³¹ Owing to the abundance of surface proteins and molecules present on cell membranes, biomimetic nanocarriers (biomimetic nanosystems based on cell membranes [BNCMs]) inherit the distinctive functionalities of their source cells, including exceptional biocompatibility, minimal immunogenicity, immunomodulatory properties, and tumor-targeting capabilities. Thus, hurdles faced by conventional nanosystems, including poor tumor targeting, short circulation time, and safety problems, are addressed, while facilitating specific and durable anti-tumor immune response. Overall, BNCMs can be exploited to promote immunotherapy by improving the delivery and application efficiency of therapeutic agents or regulating immune activities.³²

This review presents a systematic summary of BNCMs for cancer immunotherapy. We first introduce the extraordinary functions and molecular mechanisms of BNCMs derived from various cells, followed by their main preparation strategies, including isolation of cell membrane-derived vesicles, fusion of membrane vesicles (MVs) with nanosystem cores, and characterization of BNCMs. Then, a specific emphasis is placed on the application of BNCMs from the aspects of their roles in particular stages of the cancer immunity cycle. Finally, along with the analysis of existing bottlenecks for clinical translation, some suggestions for the future development of BNCMs are put forward.

BIOMIMETIC NANOSYSTEMS BASED ON CELL MEMBRANES

The background of BNCMs

The cell membrane serves as a vital boundary that separates the interior of the cell from its external environment, while also being responsible for mediating communication and interactions with the surrounding milieu. In detail, the matrix of the cell membrane is the lipid bilayer, while a variety of specialized proteins embedded in, covering, and penetrating the membrane are accountable for accomplishing the transmembrane transport and conversion of matter, energy, and information.³³ These surface proteins determine vital functions for specific cells, hence the studies of them are significant for incorporating them into nanosystem design. The most famous example is “CD47,” a transmembrane glycoprotein that inhibits phagocytosis by macrophages.³⁴ Researchers used this protein or its derivatives to couple to the surface of nanoparticles for longer circulation time in vivo. Notwithstanding the fact that many studies have focused on molecular modifications to mimic natural cellular functions, functional molecules with unknown capacities and structures are difficult to employ. Meanwhile, such a bottom-up manufacturing strategy hardly replicates the collective functions of biological systems. Therefore, a simpler top-down modification strategy has been proposed.

In 2011, for the first time, researchers utilized erythrocyte cell membranes to encapsulate the nanosystem.³⁵ This biomimetic nanosystem exhibited a distinct core-shell structure under transmission electron microscopy (TEM) and a surface potential consistent with the erythrocyte MVs. Additionally, it demonstrated excellent circulation time in vivo (elimination half-time of ≈ 40 h). Hereafter, the biomimetic approach of utilizing cell membranes to modify the surface of nanosystems has proven to be highly versatile, allowing for the integration of diverse nanomaterials with membranes sourced from various cell types. By seamlessly transferring the outer layer of cells onto the surface of nanosystems, the diversity and structural integrity of the cell membrane are preserved, empowering the biomimetic nanocarriers (BNCMs) to inherit the properties inherently possessed by the source cells.

Unique properties of different cell membranes in BNCMs

The flexibility of nanomaterials and the plentiful functions of the cell membranes complement each other, constituting biomimetic nanosystems with low immunogenicity, excellent biocompatibility, and biological targeting.^36,37 These remarkable functions are imparted by the diverse array of lipids, proteins, and carbohydrates present on the cell membrane, which vary depending on the specific type of cell (Figure 1A).

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Erythrocyte membranes

Erythrocytes are the main constituent of the blood elements, possessing blood circulation for up to 120 days.³⁸ Meanwhile, erythrocyte membranes are very simple to be extracted and purified due to the lack of nuclei and organelles. Probably for the reasons mentioned above, the first cell membranes utilized to cloak nanoparticles are erythrocyte membranes. In 2011, Hu³⁵ and co-workers coated PLGA nanoparticles with erythrocyte membrane and they demonstrated the superior circulation half-life of these state-of-the-art biomimetic nanosystems. The prolonged circulation lifespan of erythrocytes is facilitated by a diverse array of membrane proteins, including CD59 and CD47, which play critical roles in maintaining their structural integrity and evading immune clearance.^39–42 In particular, CD47 functions as a “do not eat me” signal, engaging with the signal-regulatory protein alpha (SIRPα) glycoprotein expressed on phagocytic cells, thereby inhibiting their engulfment of immune cells.⁴² Thus, nanosystems that inherit the function of erythrocytes can achieve immune evasion and long-term systemic circulation.^43–48

Platelet cell membranes

As vigilant circulators, platelets possess a myriad of functions, including hemostasis, thrombosis, and immune evasion, making them crucial responders to vascular damage and invading microorganisms. Similar to erythrocyte membranes,⁴⁹ CD47 expressed on the platelet membranes reduces the elimination of membrane-coated nanosystems.⁵⁰ Additional functional molecules on platelet membranes: P-Selection specifically bind to the CD44 receptors upregulated on tumor cells, allowing platelet membrane-coated nanosystems to actively target tumor cells.⁵¹ CD55 and CD59 act as membrane-bound complement regulators, inhibiting the immune complement system attack.⁵² All of these proteins cooperate to achieve cloaking and tumor targeting of platelet membrane-coated nanosystems.^53–60

Neutrophil membranes

As the predominant type of white blood cells, neutrophils are vital players in the innate immune system. Upon detection of chemokines, they swiftly migrate to sites of infection or inflammation, adhering to endothelial cells through integrin-mediated interactions. Subsequently, neutrophils traverse the endothelial barrier, infiltrating into tissues via intercellular gaps to execute their immune functions.⁶¹ Similarly, due to the utterly retained cell membrane component, such as LFA-1, CXCR2 and CD11b, neutrophil cell membrane-coated nanosystems can inherit the biological properties and exert the ability of intercellular communication. Consequently, neutrophils exhibit the ability to specifically target tumors⁶² and actively reprogram the immunosuppressive tumor microenvironment (TME),^63–69 fostering a more favorable immune landscape for anti-tumor responses.

Macrophage membranes

Macrophages, the “road sweeper” in the innate immune system, engulf and remove foreign components such as bacteria/viruses/pathogens that invade the body.⁷⁰ Plenty of molecules on the macrophage membranes perform their respective duties.⁷¹ The C-C chemokine receptor 2 (CCR2) can mediate the clustering of macrophage membrane-coated nanosystems at the inflammation site via the CCL2/CCR2 chemokine axis.^72,73 Meanwhile, the interaction between α4 and β1 integrins on the nanosystems and vascular cell adhesion molecule-1 expressed on tumor cells facilitates targeted delivery of the nanosystems to both primary tumors and metastatic sites, enhancing their therapeutic efficacy.^74–84 Moreover, the colony-stimulating factor 1 receptor on the macrophage membranes could deplete CSF-1 secreted by tumor cells to remodel the TME.^85,86

T cell membranes

T cells are an essential member of the adaptive immune system, with a unique TCR that recognizes antigens presented by major histocompatibility complex molecules (MHC) on the surface of antigen-presenting cells (APCs).⁸⁷ What should be noted is that MHC-presented peptides-mediated naïve T cell activation occurs only if “costimulatory” signals are received through CD28 or allied molecules.⁸⁷ In the past decade, immune checkpoint blockade (ICB) therapy has received tremendous attention. It's a kind of immunotherapy closely related to cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 inhibits T cell activation by competing with co-stimulatory receptor CD28 for binding to B7 ligation. And the PD-1/Programmed cell death ligand 1 (PD-L1) pathway plays a central role in diving T cells into a hyporesponsive phenotype known as “exhaustion.”⁸⁸ In this context, by blocking the interaction of PD-1 expressed on CTLs and PD-L1 of tumor cells, PD-1 or anti-PD-L1 antibodies on biomimetic nanosystems can be used to inhibit T cell exhaustion.^89–92 Besides, T cell membrane-coated nanoparticles are also used to deliver drugs to tumor lesions.^93,94

NK cell membranes

NK cells stand as the initial line of defense against infections and malignancies, distinguished by their rapid cytolytic capabilities. Unlike other immune cells that necessitate prolonged activation and MHC restriction, NK cells can spontaneously eliminate target cells without prior sensitization or such constraints.⁹⁵ NKG2D, DNAM1, the natural cytotoxicity receptors, and CD16 are the best-characterized activation NK cell receptors related to immune responses against cancer. NKG2D and DNAM1 can recognize certain ligands distributed on tumor cells.⁹⁶ CD16, high-affinity Fc receptors, triggers NK cells to release cytotoxicity and cytokine and lyse target cells via antibody-dependent cellular cytotoxicity. What's more, the interactions between macrophage surface receptors and NK cell membrane proteins can enhance proinflammatory M1-macrophage polarization.⁹⁷

DC membranes

Given their pivotal role in antigen presentation, dendritic cells (DCs) serve as a vital link between the innate and adaptive immune systems.⁹⁸ Initially, DCs discern antigens utilizing pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors, and C-type lectin receptors (CLRs). They then encapsulate these antigens via targeted phagocytosis and non-specific micropinocytosis, initiating the immune response.^99,100 Following proteolytic digestion into small peptides of appropriate size and sequence, the antigens are loaded onto MHC molecules for presentation to T cells, thereby activating the adaptive immune response.^100,101 Then, DCs migrate to secondary lymphoid organs where they present the MHC-peptide complexes on their surface to either CD8⁺ or CD4⁺ T cells, thereby triggering the initiation of targeted immune responses. Meanwhile, T cell cytokines secreted by DCs^102,103 and appropriate co-stimulatory signaling mediated by CD80/CD86¹⁰⁴ are given simultaneously to promote activation. In consequence, the DC cell membrane-coated nanosystems acquire the innate capability to specifically target lymph nodes., present antigens, and prime T cells.^105–109

Tumor cell membranes

The abundant proteins on the tumor cell endow the biomimetic nanosystems based on the tumor cell membrane with many capabilities, such as immune escape, homotypic tumor targeting, and tumor-specific-immune activation.^110,111 CD47, a widely expressed glycoprotein on the tumor cell membrane, can effectively bind to the surface SIRPα receptor on phagocytes to avoid macrophage-mediated phagocytosis.¹¹² Thomsen–Freidenreich antigens,¹¹³ Galectin-3,^113,114 cadherin, integrins, and epithelial cell adhesion molecule¹¹⁵ play synergistic roles in homologous targeted enrichment of nanosystems.^116–124 Additionally, the tumor cell membrane-anchored tumor antigens serve as a rich source of tumor-associated antigens (TAAs), capable of eliciting robust and tumor-specific immune responses. These antigens can be harnessed to develop more potent vaccines, thereby bolstering their efficacy in combating cancer.^125–128

Bacteria membranes

Due to the additional cell wall, bacteria cell membranes are usually obtained by MVs released from bacteria. Circular exosomes, with diameters ranging from 20 to 250 nanometers, play pivotal roles in facilitating cell-to-cell communication, enhancing virulence, mediating horizontal gene transfer, exporting cellular metabolites, and participating in phage infection processes.¹²⁹ Despite the fact that MVs are produced by both Gram-positive and Gram-negative bacteria, our understanding of the biogenesis and composition of MVs in Gram-positive bacteria lags significantly behind that of their Gram-negative counterparts.¹³⁰ Gram-negative bacteria generate outer membrane vesicles (OMVs) that encapsulate an array of bioactive molecules, including enzymes, virulence factors, bacteria-specific antigens, and diverse pathogen-associated molecular patterns (PAMPs) like lipopolysaccharides (LPS) and lipoproteins.^131–134 Due to the wide range of surface bacterial antigens, ample PAMPs, and the proper size, OMVs have apparent advantages in the application of vaccines^135–137 and immune adjuvants.^138–141 On the one hand, the proper size would likely facilitate uptake by APCs and entry into lymph nodes.¹⁴² On the other hand, bacterial-associated PAMPs interact with the PRRs on APCs, inducing a long-lasting immune response.¹⁴³ Additionally, some bacteria like Listeria, Clostridium, and Salmonella use unique mechanisms to target solid tumors,¹⁴⁴ thus their MVs are promising to be further leveraged for tumor targeting.

Hybrid cell membranes

Recently, cell membranes of different origins or liposome membranes are fused to fabricate hybrid cell membranes with superimposed functions for performing increasingly complex tasks in dynamic TME. Hybrid cell membranes have at least two or more biological functions: the targeting ability and the specific function conferred by the other membranes.¹⁴⁵ Specifically, cancer cell membranes and platelet membranes can impart tumor targeting to biomimetic nanosystems.^146–149 The latter functions mainly cover immune evasion by immune cell membranes,^150,151 immunomodulation by bacterial cell membranes,^152,153 and enhanced loading by liposomes.^154–158 Overall, the diverse permutations between different membranes create amazing effects, synergistically improving anti-tumor efficiency.^159–162

Engineered cell membranes

Since the source of cell membranes is derived from living cells, they can be chemically modified and genetically engineered to have more diverse functions.¹⁶³ Abundant motifs possessed by the cell membrane can be exploited for binding, such as amino, carboxyl, and sulfhydryl groups, thus conferring additional capacities to biomimetic nanosystems.^93,164–166 This strategy offers a high degree of flexibility but will face the obstacles of impaired biological activity of proteins and inadequate protein coupling.^166,167 Genetic engineering, which regulates specific cell membrane protein expression by introducing exogenous genes, preserves the integrity and orientation of protein and facilitates the efficient biomedical application of engineered cell membrane-coated nanoparticles.^{84,91,168–175} Rather, its limitations are complexity and unpredictability.¹⁷⁶

Preparation of the BNCMs

The preparation of BNCMs primarily encompasses three key steps: isolation of cell membrane-derived vesicles, synthesis of nanosystem cores, and fusion of MVs with the cores. To validate the successful fabrication of biomimetic nanosystems, their characteristics are also analyzed. Considering the complexity of the cores, in the following sections, we will focus on the isolation and fusion methods of cell membrane-derived vesicles, while characteristics analysis techniques of BNCMs will be mentioned as well (Figure 1B).

Isolation of cell membrane-derived vesicles

The initial stage of isolation commences with acquiring cell membrane materials from a suitable source, be it blood, tissue samples, or culture dishes. When dealing with cells that are scarce within the body, additional enrichment procedures are necessary. Once a sufficient quantity of source cells is obtained, the subsequent step involves lysing these cells to facilitate the extraction of their membranes.³² Common cell lysis protocols include sonication, freeze and thaw, extrusion, and hypotonic solution buffer. Before choosing the cell lysis protocols, how to obtain cell membranes maintaining intact proteins with full functionality should be deliberated.¹⁷⁷ For anucleate cells, the cell membrane can be obtained simply by single lysis protocols and centrifugation. Conversely, the isolation process is more intricate for nucleated cells, owing to their additional cell nucleus and organelle. After using a combination of lysis protocols to destroy cells, cell membranes are purified by using discontinuous sucrose gradient centrifugation to remove their intracellular biological macromolecules, organelles, and cell nucleus.³⁶ The last step is washing the pellet several times with phosphate-buffered saline buffer solution and repeatedly extruding via polycarbonate porous membranes to obtain empty vesicles.

Fusion of MVs with nanosystem cores

After purification, MVs can be fused to synthetic cores. The purpose of this process is to transfer the specific membrane proteins of source cells to the surface of BNCMs. What calls for special attention is the electrostatic interactions between cores and cell membranes. Owing to electrostatic repulsion between similarly charged entities, negatively charged cores and MVs naturally arrange themselves into spherical particles, exhibiting a core-shell structure.¹⁷⁸ More precisely, the abundance of negatively charged groups adorning the cell membrane surface drives the cores to interface with the less negatively charged segments of the membrane. This process meticulously constructs biomimetic nanosystems featuring a right-side-out membrane configuration, guaranteeing the optimal display of polysaccharides and proteins towards the exterior milieu.^179,180 Conversely, in the blend of positively charged cores and vesicles, aggregation emerges. This is likely due to the robust electrostatic attractions that disrupt the precise local arrangement necessary for lipid encapsulation, hindering the formation of desired structures.¹⁷⁸

Many different methods can be utilized to produce BNCMs, ranging from co-extrusion to sonication and electroporation. Co-extrusion is a labor-intensive approach in which synthesis cores suspension and MVs are co-extruded multiple times through polycarbonate porous membranes with different pore sizes.¹⁸¹ The fluidity of the membrane plays a pivotal role in reforming a stable core-shell structure by mechanical force. Notwithstanding the advantages of co-extrusion to achieve uniform size distribution and minimize the denaturation of membrane proteins, large-scale production is still challenging owing to the tedious steps.¹⁸² Sonication is another effective alternative by using ultrasonication to disrupt the MVs and further promote the recombination of membrane and cores.¹⁸³ However, the intense ultrasounds energy can induce damage to the structural integrity and bioactivity of the cell membrane and the destruction of cores.¹⁸⁴ Therefore, during this operation, the parameters such as frequency, power, and duration need to be considered cautiously.¹⁸⁵ Furthermore, electroporation can also promote the formation of micropores on the MVs and facilitate the entry of biomolecules and nanosystem cores to fuse the MVs with cores.¹⁸⁶ It can be further combined with microfluidic devices to produce BNCMs as well.^187,188 In addition to the methods mentioned above, a novel method for fabricating biomimetic nanosystems by passing cores through a concentrated lipid layer prepared by density gradient centrifugation has also been proposed.

Characterization of the BNCMs

To ensure the structural and biological functional integrity of the membrane, physiochemical and biological characterizations of the BNCMs need to be analyzed. Incomplete or unstable cell membrane coating may cause exposure of contents, resulting in accelerated clearance of therapeutic agents and unwanted side effects. Under this circumstance, several physiological techniques can be used to verify whether the intact and steady core-shell structure has been formed. Primarily, the size and surface charge of BNCMs can be measured by particle size zeta potentiometer based on dynamic light scattering. An increment in size and negative charge close to that of the cell membrane derived-vesicles can be observed after successfully fusing the MVs with cores.^189,190 Next, multiple microscopic techniques including TEM, scanning electron microscopy (SEM), and confocal laser scanning microscopy (CLSM) can visualize the surface of prepared nanosystems, in a more intuitive manner to display the changes. More specifically, TEM imaging of completely coated nanosystems reveals a core and a lighter outer membrane.^98,191 Likewise, using SEM, plicated membranes on the surface of the nanosystems can be observed.^192,193 For CLSM, cell membranes and inner cores are separately tagged with different fluorescent, due to the core-shell structure, fluorescence colocalization images present the overlap of two fluoresces.^194,195 Lastly, spectroscopy can also serve as an alternative to qualitatively characterize cell membrane coating by comparing spectra before and after coating. The two common spectroscopies are ultraviolet-visible spectroscopy and Fourier transform-infrared spectroscopy.¹⁹⁶

The key for BNCMs to inherit diverse source cell-relevant functions is maintaining the dynamic and intact proteins and right-side-out orientation of the coated membrane. Therefore, the quality and orientation of cell membranes require to be evaluated by biological techniques for the improvement of therapeutic efficiency. From the perspective of protein analysis, sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and Coomassie brilliant blue staining can be applied to identify and quantify the proteins on the cell membranes. Among all of them, SDS-PAGE is the most widely used for qualitative and rough quantification of proteins.⁸⁶ And more precise quantitative analysis is achieved by flow cytometry which can measure the fluorescent intensity produced by the membrane proteins tagged with fluorescent antibodies.⁹⁰ Regarding the determination of cell membrane orientation, key methodologies encompass immunogold staining, antibody binding assays, as well as quantitative analysis of glycoproteins and sialic acid content. The first two techniques can study the orientation of the coated membrane by identifying the location of specific proteins,^194,197 while the latter technique achieves its objective by quantifying glycoproteins and sialic acid, both of which exhibit asymmetric distribution on the exterior surface of the cell membrane.^178,198

APPLICATION OF BNCMS FOR CANCER IMMUNOTHERAPY

An effective antitumor immune response necessitates the promotion of a meticulous, sequential series of events collectively referred to as the cancer-immunity cycle. To be specific, the process of cancer-immunity cycles generally contains: (1) antigens released by tumor cells and captured by DCs; (2) DCs process and present antigens to T cells; (3) T cells are primed and activated by tumor antigens; (4) the activated effector T cells traffic and infiltrate into the tumors; (5) tumor cells are specifically recognized and killed by effector T cells; (1) killing of tumor cells promote more tumor antigen release, leading to the subsequent revolutions of the cycle.¹⁹⁹ Initiating or reinitiating the self-sustaining cancer-immunity cycle is the primary tool of cancer immunotherapy, any losing process will result in unsatisfactory therapeutic results.²⁰⁰

Various cell membranes and inner cores are combined to target specific events of cancer-immunity cycles. Current strategies mainly contain: (1) promoting tumor cells to release tumor antigens through the immunogenic cell death (ICD); (2) increasing APCs presentation; (3) regulating T cells, including enhancing activation and inhibiting exhaustion; (4) modulating the immunosuppressive TME. In the following sections, existing literatures will be classified according to the main role of cell membrane coatings in cancer immunotherapy (Figure 1C).

Promoting TAAs release through the ICD

ICD, induced by modalities such as phototherapy, radiotherapy, and chemotherapy, prompts the release of TAAs and danger-associated molecular patterns (DAMPs), notably including ATP, high-mobility group box-1 (HMGB1), heat-shock proteins (HSPs), and calreticulin (CRT). Remarkably, the surge of ATP within the TME serves as a “find me” signal, luring immune cells towards dying tumor cells. Additionally, CRT migrates to the tumor cell surface, enhancing antigen recognition by DCs, thereby acting as an “eat me” signal. Extracellularly released HMGB1, functioning as a “danger signal,” binds to Toll-like receptor 4 (TLR4), which not only aids in antigen presentation by DCs but also stimulates the activation of cytotoxic T cells.^201,202 To avoid off-target effects and undesired clearance in vivo, biomimetic nanosystems based on different cell membranes can be adopted to enhance the tumor-targeting and evading immune clearance of ICD inducers. In that case, nonimmunogenic cells will be transformed into immunogenic cells, and further initiate the cancer-immunity cycle.

Chemotherapy

Chemotherapy drugs including anthracyclines (such as doxorubicin and mitoxantrone), DNA damaging agents (such as oxaliplatin), and proteasome inhibitors (such as bortezomib) are widely leveraged to cause chemotherapy-mediated cytotoxicity and restore the immunogenicity of tumor cells. However, delivery obstacles, such as low water solubility, off-target effects, and non-specific biodistribution, have hindered the widespread application of chemical ICD inducers.^203,204 In that case, application of biomimetic nanosystems can be an effective solution for safe, efficient, and specific delivery.^205–207 The presence of the extracellular matrix (ECM) around tumor cells poses a dual challenge: it obstructs the interstitial transport of nanosystems and impedes the effective dissemination of oxygen, ultimately inducing tumor hypoxia and diminishing the therapeutic potency of chemotherapy drugs. To address this issue, Qiao et al.²⁰⁸ exploited transforming growth factor beta (TGF-β) receptor inhibitor LY364947 to reduce the expression of collagen I for improving the penetration of nanosystems and reliving hypoxia. They coated doxorubicin (DOX) and LY364947 loaded zeolitic imidazolate framework-8 with erythrocyte membrane to develop a biomimetic metal-organic framework (MOF) nanodrug (ZIF-8-DOX-LY-RM). First, the biomimetic functions of the red cell membrane allowed the enrichment of ZIF-8-DOX-LY-RM in tumor tissues. Then, TGFBR1 was released to loosen the intricate structure of the ECM. Ultimately, adequate oxygen supply alleviated hypoxia-mediated chemoresistance, thus significantly improving the chemotherapeutic efficacy of DOX.

Furthermore, co-delivery of STING agonists and chemotherapy drugs could also serve as a promising strategy to boost the antitumor efficiency. Two primary hurdles in achieving optimal treatment outcomes for acute myeloid leukemia (AML) encompass chemotherapy resistance and the complex tumor immune microenvironment. In the study of Wang et al.,²⁰⁹ they constructed a leukemia cell membrane-camouflaged hollow MnO2 nanocarrier (HM) with encapsulated DOX to surmount these barriers. After internalization by cells, disassembly of this biomimetic nanomedicine (LHMD) was triggered by the high levels of GSH and endosomal acid in tumor cells, followed by the release of DOX and Mn²⁺. Mn²⁺ exhibits dual beneficial effects: it significantly enhances MRI signals for AML detection, while also activating the STING pathway and sensitizing cGAS to recognize double-stranded DNA breaks induced by DOX.

Additionally, leveraging two kinds of chemotherapeutics agents at the same time may also result in striking therapeutic efficacy. As reported in the study of Guo et al.,²¹⁰ they constructed the redox-responsive GCT@CM NPs to amplify the chemotherapeutic efficacy of both phosphorus dendrimer–copper (II) complexes 1G₃-Cu and toyocamycin (Toy). 1G₃-Cu complexes were first assembled with the poly(ε-caprolactone)-SS-methoxy poly (ethylene glycol) (PCL-SS-PEG) to form 1G₃-Cu loaded nanoparticles (GC NPs), and then Toy was encapsulated into GC NPs with the help of hydrogen bonding. After that, the entire inner core was camouflaged by the tumor cell membrane. After intravenous injection, GCT@CM NPs were able to accumulate in tumor tissues owing to the homologous targeting of tumor cell membranes. Under the GSH-rich TME, redox-responsive dissociation of the biomimetic nanoparticle (BN) occurred followed by a rapid release of the loaded drugs. The synergistic effect of Toy-mediated ER stress exacerbation and 1G3-Cu-triggered mitochondrial dysfunction significantly triggered tumor cell apoptosis and intensified ICD, thereby promoting DC maturation and potentiating antitumor immune responses (Figure 2A).

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Radiation therapy

Analogously, radiotherapy augments immune systems’ recognition of tumors, fostering a more diverse and robust antitumor T cell response. Pei et al.¹⁵³ designed a hybrid nanoplatform (MGTe) composed of glutathione decorated Te nanoparticles (GTe) and hybrid cell membrane coating formed by fusing tumor cell membranes (TM) and bacterial outer membranes (BM). First, BM and TM collaborated to overcome immune-suppressing barriers, effectively stimulating both innate and adaptive immunity for a potent tumor antigen-specific response. Second, GTe acted as a radiosensitizer, enhancing radiotherapy's effectiveness by inducing ROS production and augmenting ICD. What's more, Patel and co-workers²¹³ proposed a multifunctional bacterial membrane-coated nanoparticle (BNP) to enhance antigen retrieval. The BNP were consisting of four parts: maleimide groups modified on the cell membrane surface for enhanced antigen uptake; the outer layer derived from Mycobacterium smegmatis to stimulate innate immunity and DC maturation; anionic CpG (TLR9 agonist) and pH-responsive polymer PC7A (endosome disruption) loaded in the inner polyplex. Initially, radiation therapy was administered to release abundant TAAs, which were subsequently sequestered by maleimide moieties. This synergy, along with CpG and bacterial cell membranes abundant in PAMPs, bolstered antigen uptake by DCs. Upon internalization within the acidic endosomal environment, PC7A was liberated, fostering escape and facilitating cross-presentation, ultimately stimulating potent antitumor T cell responses. The treatment of RT + BNP verified the capacity to increase the proportion of activated effector T cells, boost Type I IFN response, and upregulate the expression level of MHCⅠ in the TME was verified. At the same time, effective antitumor immune memory was also established in the mice bearing immunologically “cold” syngeneic tumors.

Phototherapy

Phototherapy, encompassing photothermal therapy (PTT) and photodynamic therapy (PDT), harnesses phototherapeutic agents to generate heat or cytotoxic reactive oxygen species (ROS) upon light illumination. This modality selectively eradicates tumor cells in a non-invasive fashion, minimizing collateral damage to adjacent normal tissues.²¹⁴ Employing cell membranes to cloak phototherapy-based nanoparticles is a strategic approach to attain immune evasion, prolong blood circulation, and intensify tumor targeting, thereby augmenting the overall anticancer therapeutic efficacy.^215–220

During PTT, photothermal agents (PTAs) are able to generate heat when irradiated with an externally applied, leading to the thermal ablation of tumor cells. The widely used PTAs include noble metallic nanomaterials (such as gold nanorods, and Pd nanosheets), semiconductor nanoparticles (such as CuS), organic near-infrared (NIR) absorbing dyes (such as indocyanine green (ICG), IR780, IR820, and IR792) and polymer nanoparticles (such as polydopamine, polypyrrole, and melanin-like nanoparticles).^221,222 Chen and co-workers²²³ developed cell membrane-derived nanoplatforms (PI@EPV) by enveloping ICG-loaded PLGA with fusion cell membrane prepared by fusing melanoma cytomembrane vesicles and attenuated Salmonella OMVs. Integration of localized elimination mediated by ICG and durable antitumor immunity stimulated by tumor-specific antigen and natural adjuvant on the cell membrane was demonstrated to have antitumor synergy. Recently, due to the high light strength, good light stability, and wide stokes shift, the aggregation-induced emission luminogens (AIEgens) have gained extensive public attention.^224,225 Outstanding AIEgens possess a variety of properties, such as photoacoustic (PA) imaging, and phototherapy of tumors. For instance, Cui and co-workers²¹¹ designed a biomimetic photothermal nanoparticle featuring both second near-infrared (NIR-II) fluorescence emission and excellent photothermal conversion, called DHTDP. Through elaborate design of its intramolecular interactions and distortions in molecular conformation, its core AIEgens have enhanced AIE propensity, NIR absorption, NIR II emission, significant PA signals and remarkable photothermal conversion behaviors. Ultimately, tumor cell membrane camouflage was then applied to endow it with homologous targeting capabilities, enabling superior phototherapeutic diagnostic capabilities (Figure 2B).

PDT leverages photosensitizers (PSs) activated by light in the presence of oxygen (O2) to generate cytotoxic ROS, which subsequently oxidize nearby biomolecules, resulting in tumor cell death. Organic PSs (such as porphyrins, indocyanine dyes, and BODIPYs), Pc, natural products, metal complexes (such as RuII complexes and AuIII complexes), MOF, and meta-based nanostructure are typical photosensitizers.^226,227 Similarly, improved delivery of PSs by biomimetic nanosystems can be exploited to eradicate primary tumors with photo-triggered generated ROS. Furthermore, ICD-induced release of TAAs and DAMPs would provoke the tumor-specific immune response synergistically stimulate a more intense anti-tumor response with the biomimetic nanosystems, killing residual or metastatic tumor cells. In the study of Zhuang and co-workers,²²⁸ escherichia coli MG1655 derived OMVs are fused with the thylakoid nanovesicles (NTs) of spinach to fabricate the bacteria-plant hybrid nanovesicles. The component derived from the plant-derived thylakoid membranes (Tk) that contained ample enzymes and photosystems could produce efficient photodynamic effects. Moreover, the OMV components encompass a diverse array of immunostimulatory molecules that evoke antigen-specific immune responses and restrain tumor growth. Likewise, AIEgens exhibit advantages in terms of high emission efficiency and aggregated state photosensitivity. Xu et al.²²⁹ synthesized a photoactive antigen-presenting platform (DC@AIEdots) by coating DC cell membrane on nanoaggregates of the AIEgens for cancer photon-immunotherapy. Remarkably, the DC membrane layer enhances T cell proliferation and activation, enabling DC@AIEdots to hitchhike on endogenous T cells, clustering efficiently around tumors. This boosts tumor delivery of AIE photosensitizers by 1.6-fold. Concurrently, PDT is achieved within tumor cells by accumulated AIE photosensitizers. DC@AIEdots not only elicit an antitumor immune response to suppress both primary and distant tumors but also establish long-term immune memory, guarding against tumor recurrence.

Other therapies

Sonodynamic therapy (SDT), mediated by sonosensitizers, generates substantial ROS under ultrasound, triggering ICD in tumors. Harnessing the non-invasive nature of ultrasound, SDT has garnered attention in diverse preclinical tumor models. Xie et al.²³⁰ constructed a biomimetic self-delivery nanodrug (HB-NLG8189@MPCM) constituted of HB (a new clinical photosensitizer) and NLG8189 [indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor] self-assemble nanodrug and the macrophage cell membrane layer. Hence, immunotherapy synergizes with SDT to achieve highly effective inhibition of tumor growth. Zhang and co-workers²³¹ applied homologous adjuvant-embedded cancer cell membrane to the self-assembly Ag₂S QDs and amphiphilic polymers Pluronic F-127, eventually fabricating BN-Ag₂S@P@CM-A for NIR-II fluorescence imaging-guided sonodynamic-immune combination therapy. Meanwhile, Sun et al.²³² designed a poly (lactic-co-glycolic acid) (PLGA)-based cancer vaccine which were consisting of messenger RNAs (mRNAs), sonosensitizer chlorin e6 (Ce6), tumor cell membrane outer layer. Under US irradiation, the escape of mRNA from endosome in antigen pretention cells was promote. Owing to their properties of disturbing splicing resembling the metastatic cells, neoantigens of metastatic cancer was provided in advance. Through 4T1 syngeneic mouse model, the nanovaccine was demonstrated to promote antigen presentation, induce effective anti-tumor immunity and prevent cancer metastasis.

Ferroptosis as a type of programmed cell death, can induce the release of TAAs and establish immunogenic TM, which, in turn, produces a robust antitumor therapeutic effect in conjunction with immunomodulation. As reported by Zhang and co-worker,¹⁶⁴ a biomimetic magnetosome (Pa-M/Ti-NC) was developed to enhance the collaborative therapeutic effects of ferroptosis/immune-modulation. Fe3O4 magnetic nanocluster (MNC) acted as the inner core, leukocyte membranes played the role of the cloak, TGF-β inhibitor (Ti) was loaded in the cell membrane and PD-1 antibody (Pa) was attached to the membrane surface, they collectively form engineered magnetosomes loaded with Fe, Pa, and Ti. After intravenous injection, magnetosomes accumulated in the tumor tissues and elicited an immune response. Additionally, Li and co-workers²³³ coated glycyrrhetinic acid (GA) loaded PLGA with the leukocyte membrane to construct GCMNPs. GA encapsulated in GCMNPs could inhibit GSH-dependent GPX4 expression to induce ferroptosis. Subsequently, ICD was caused and TAAs were released, resulting in the maturation of DCs and activation of anti-tumor CD4/CD8 T cell immunity as well.

Combination therapy

Different tumor treatment modalities have their own strengths, and different combinations may create unexpected synergistic therapeutic effects.^234,235 Gao and co-workers²¹² constructed biomimetic nanodevices (ICG@CCM-AuNC-PO₂-Hb) which are capable of secreting smaller-sized cell membrane-derived nanovesicles in situ under near-infrared laser irradiation for synergistic photothermal/PDT. Phase transitable perfluorohexane (PFO) and hemoglobin (Hb) was loaded by photothermal AuNC with hollow and porous structures, and then the obtained nanpsystems were pre-saturated with oxygen. Subsequently, they were encapsulated with ICG-anchored 4T1tumro cell membranes. Following tail vein injection, the biomimetic nanodevice enables homologous targeting through the tumor cell membrane, accumulating in the tumor tissues. Upon exposure to near-infrared laser ligh, the loaded PFO undergoes a phase transition in response to the surface plasmon resonance effect generated by the AuNC framework. Therefore, the gaseous PFO is blasted from the etched pores of AuNC, generating nano-vesicles with smaller size, adequate oxygen supply and anchored ICGs for further self-contained oxygen-enhanced PDT and PTT. Considering that light is difficult to penetrate deep into tumor tissues, limiting the efficacy of phototherapy (Figure 2C). Kang and colleagues²³⁶ designed a self-accelerating nanoplatform that combines phototherapy with chemotherapy for multifunctional image-guided combination immunotherapy. To be specific, methoxy-substituted AIEgens with enhanced fluorescence and PA brightness were conjugated to nanoparticles with a paclitaxel (PTX)-based hypoxia-responsive prodrug and further camouflaged with M1-type macrophage membranes. For one thing, this biomimetic nanosystem complements the advantages of fluorescence and PA imaging, allowing for more sensitive and accurate tumor imaging; for another thing, PDT exacerbates tumor hypoxia, triggering PTX release and promoting anti-tumor immune responses. What's more Lu et al.²³⁷ developed a bioinspired nanometal organic framework (AMR-MOF@AuPt) that combines SDT, chemodynamic therapy, and immunotherapy. This novel nanosystem has three layers of core-shell structure, to be specific, the inner core is the Mn²⁺-based nano MOF loading immunoadjuvant resiquimod (R848), thin AuPt shell formed by reducing Au and Pt atoms is in the middle, the outermost layer is anti-DEC205 engineered Hep1-6 tumor cells membrane. AMR-MOF@AuPt can directly target DCs through anti-DEC205 and then achieve sono-immunotherapy, at the same time, deep tissue-penetrating sonication can mediate large amounts of reactive oxygen produced by AuPt shell and nano MOF to kill tumor cells.

Increasing APCs presentation

APCs, notably macrophages, DCs, and B cells, are pivotal in innate and adaptive immunity. Among these, DCs stand out as the pivotal mentors of T cells. Immature DCs initiate the process by recognizing and capturing antigens, subsequently processing them into small peptides and presenting these peptides via MHC molecules. This presentation of MHC-peptide complexes to helper and effector T cells triggers a tumor-specific immune response. Furthermore, upon maturation, DCs amplify the immune response by recruiting and activating T cells within draining lymph nodes.

However, tumor immunosuppressive microenvironment and antigen immunogenicity reshaping caused by cancer immunoediting hinder DCs from effective antigen presentation. For one thing, IL-6, IL-10, and tumor exosomes in the TME inhibit DC maturation. For another thing, defects in tumor antigens impair the uptake and presentation by DCs.²³⁸ To improve the situation, the cancer vaccine is utilized for delivering sufficient antigens to provide more adequate antigenic stimulation and elicit potent anticancer immunity for the specific killing of tumor cells. Due to several excellent capacities, BNCMs have been designed as the antitumor vaccine to irritate DCs for cancer immunotherapy. First, plenty of immunogenicity or immunostimulatory molecules on cell membranes can serve as cancer vaccines to stimulate DC maturation, boosting anti-tumor immune response.²³⁸ Second, antigen presentation via BNCMs to DCs enhances cross-presentation efficiency. Cross-presentation, which means the presentation of exogenous antigens on MHC class Ⅰ molecules, is vital for facilitating the adaptive immune response.²³⁹ Antigens loaded by nanosystems access DCs via phagocytosis and can present antigens more efficiently by MHCⅠ. Soluble antigens, however, internalized by the macropinocytosis pathway are generally poorly presented to MHCⅠ, thus exhibiting low efficiency of cross-presentation.²⁴⁰

Capitalizing on the rich array of tumor-derived antigens present in cell membranes isolated from tumor cells, biomimetic nanosystems cloaked with tumor cell membranes are widely employed as cancer vaccines, directing the immune system to identify and eliminate cancerous cells. It is worth mentioning that using autologous antigens can elicit antitumor immunity beneficial to the individual patient.^239,240 By harnessing autologous tumor cell membranes, a diverse array of patient-specific tumor antigens can be presented, enabling precise homologous targeting and instigating a robust, tumor-specific immune response. Rao and co-workers²⁴¹ validated the effective targeting of gelatin nanoparticles coated with patient-derived tumor cells (PDTC) membranes from head and neck squamous cell carcinoma (HNSCC) against syngeneic tumor cells and tissues in a patient-derived xenograft (PDX) model. Conversely, a mismatch between the cell membrane of the donor cell and that of the host cell results in weak targeting. Adoptive cellular immunotherapy (ACT) offers immense potential in treating a broad spectrum of malignancies, particularly tumors. This approach involves the reinfusion of autologous immune cells, which have been meticulously engineered and expanded ex vivo, to directly elicit potent tumor-rejecting immune responses.²⁴² Xiao et al.²⁴³ conceived an innovative strategy to unite neoantigen-loaded nanovaccines (M-NP-Ag) with adoptive DC transfer for improved immunization efficiency in a personalized manner. Biodegradable neoantigen-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles were coated with the tumor cell membrane to develop nanovaccine, while autologous tumor lysate-loaded DC vaccine (DCV) was prepared through an in vitro manufacture process. This hybrid injection strategy allowed co-delivery of identified neoantigens and undefined antigens derived from autologous tumor lysates, thereby initiating anti-tumor T cell immunity in a personalized manner.

On account of antigens alone being poor inducers of adaptive immunity, the presentation of tumor antigens alone may not able to overcome the immunosuppressive TME, so immunostimulatory adjuvants are incorporated into vaccines to increase the vaccine efficacy.²⁴⁴ Thereinto, small molecules of TLR agonists are commonly encapsulated into the core of the nanosystems as immune adjuvants.^{126,165,245–247} Capitalizing on the nucleic acid absorption of aluminum phosphate (AP), Gan and co-workers¹²⁵ fabricated CpG loaded and B16F10 tumor cell membrane-coated aluminum phosphate nanoparticles (APMC). The lymph targeting cancer vaccine could enhance the co-delivery of antigens and adjuvants into APCs and stimulate their maturation (Figure 3A). Immunization of mice triggered CTL-mediated tumor-specific killing, effectively suppressing tumor growth and enhancing the survival of tumor-bearing animals.

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The biochemical hallmarks of ICD, such as CRT and HSP displayed on the cell membrane, emit “eat me” signals that augment antigen phagocytosis. Consequently, nanoparticles encapsulated with tumor cell membranes enriched in ICD-associated proteins can potentiate the uptake, maturation, and activation of DCs.^122,249,250 Tuo et al.²⁴⁸ innovatively employed irradiated tumor cell membranes, which owned more MHCⅠ molecules and abundant DAMPs, to coat R837 loaded PLGA inner core, preparing nanovaccine (RP@RMs) with the capacity of enhancing the antigen presentation efficiency (Figure 3B). Due to the strong immunogenicity of RP@RMs, the proportion of matured DCs was increased. RP@RMs have been validated to enhance antitumor immune responses, thereby augmenting the effectiveness of anti-PD-1 therapy.

Furthermore, the pairing of agonistic antibodies with tumor vaccines emerges as an efficacious strategy to accelerate DC maturation, fostering robust adaptive immune responses. Li et al.²⁵¹ constructed anti-CD40 single-chain variable fragment (scFv)-anchored tumor cell membranes by the genetic engineering approach to address the shortcomings of existing tumor cell-derived vaccines due to the lack of co-stimulatory signals leading to central immune tolerance (Figure 4A). CD40, a member of the tumor necrosis factor receptor superfamily, is abundantly expressed on APCs. Its engagement with the CD40 ligand triggers a pivotal cascade that initiates DC maturation, characterized by upregulated co-stimulatory molecules, enhanced antigen cross-presentation, and robust cytokine production. Subsequently, it would trigger T cell activation and differentiation, provoking a more robust anti-tumor immune response. The anti-CD40 scFv-anchored membrane-coated nanovaccine (Nano-AAM/CD40) has demonstrated remarkable antitumor efficacy across both “hot” and “cold” tumor models, underscoring its broad therapeutic potential.

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Bacterial membranes are naturally endowed with adjuvant properties, featuring diverse PAMPs derived from proteins, lipids, and glycans. These PAMPs are recognized by innate immune cells, eliciting intricate intracellular signaling cascades that culminate in the production of proinflammatory cytokines and chemokines.^254,255 In this context, to succeed and potentiate the immunological functions of the components, bacterial outer vesicle and tumor cell MV were fused to fabricate the hybrid fusion vesicles. This tumor antigenic nanoplatform with self-adjuvanting not only promotes activation and maturation of APCs but also maximized antitumor effects mediated by CTLs. In the study of Ke et al.,²⁵⁶ bifunctional fusion membrane nanoparticles (FM-NPs) composed of autologous tumor cell membranes and Mycobacterium phlei membranes are exerted to synthesize DCs activation hydrogel. Afterward, granulocyte-macrophage colony-stimulating factor (GM-CSF) and FM-NPs are loaded in an injectable alginate hydrogel. Due to the in vivo cations, after the subcutaneous injection, in situ hydrogel could be formed. GM-CSF was first released to recruit naïve DCs to the hydrogel, subsequently, M.ph membrane and tumor cell membrane components in FM-NPs were able to stimulate DC maturation and provide tumor antigens, respectively. Ultimately, converting “cold” tumors featured by lacking tumor-infiltrating T cells and Immune insensitivity into “hot” inflamed tumors. In addition to this, Chen et al.²⁵² fused tumor cell membranes (TMs) from resected autologous tumor tissues and Escherichia coli cytoplasmic membranes (EMs) to create the hybrid membrane nanoparticle vaccine (HM-NPs) for simultaneous delivery of antigen and adjuvant to DCs (Figure 4B). Therefore, HM-NPs are capable of provoking innate and tumor-specific immune responses without severe side effects. In the multiple murine tumor models, HM-NPs prevented tumor recurrence and established long-time protection against tumor rechallenge. Additionally, bacterial outer membrane vehicles can be further leveraged after genetic engineering or chemical modification. Nie's team utilized genetic engineering and “Plug-and-Display” technology to design a flexible tumor vaccine platform based on OMVs.

By fusing various protein catchers with ClyA, a prevalent protein on the OMVs surface, ligands linked to protein tags can be swiftly displayed on the vaccine vector. This primarily showcases tumor antigens, thereby provoking a targeted antitumor immune response.²⁵² The efficient accumulation of OMVs in draining lymph nodes, coupled with their stable integration of antigens, ensures robust DC activation and subsequently induces T cell-mediated antitumor immunity. Afterward, the “Plug-and-Display” strategy was employed in fabricating the therapeutic mRNA vaccine (OMV-LL-mRNA).²⁵³ The fusion of RNA-binding protein L7Ae and listeriolysin O (LLO) to ClyA respectively facilitated box C/D-mRNA binding and enhanced endosomal escape, thereby promoting subsequent mRNA translation. These engineered OMVs efficiently delivered mRNA tumor antigens into DCs for translation, leading to successful antigen processing and presentation. Notably, the robust antitumor adaptive immunity observed across multiple tumor models underscores the versatility and potential of this approach in mRNA vaccine development (Figure 4C). Similarly, this genetically-engineering-based modular approach can be applied to other BNCMs to enhance tumor-targeted drug delivery.²⁵⁷

Regulating T cells

Enhancing activation of T cells

In vivo, T cell activation relies on three fundamental signals. Initially, antigen recognition prevails as T cell receptors discern MHC-peptide complexes presented by APCs. Subsequently, the CD28-B7 complex, a pivotal co-stimulation signal, activates T cells fully through CD28's interaction with APC-expressed B7 ligands. Finally, cytokines produced by APCs and helper T cells are crucial for sustaining cytotoxic T lymphocyte (CTL) survival, completing the intricate process of T cell activation. Overall, the induction of T cells highly depends on the interaction with APCs²⁵⁷ Under these circumstances, patients were vaccinated with APCs to stimulate T cells and induce immunological memory for controlling tumor relapse.

Multiple clinical trials have yielded promising results, notably the approval of Sipuleucel-T by the US Food and Drug Administration for managing metastatic prostate cancer. Nonetheless, the process of isolating and stimulating autologous APCs ex vivo is both time-consuming and costly, while the quality of these APCs generated outside the body remains unpredictable and uncontrollable.^258,259

To bypass the challenges associated with autologous APCs, researchers have devised innovative scaffolds and nanoparticles, collectively termed artificial APCs (aAPCs), which mimic the function of DCs in priming T cells. This approach offers an alternative strategy to enhance T cell activation. Requisite biological signals, including MHC proteins and costimulatory markers, are engineered to display on the surface of nanosystems. This strategy bypasses the requirement of traditional antigen processing and presentation²⁶⁰ and also eliminates concerns associated with the derivation, manipulation, and re-administration of autologous APCs. Further, as a simpler and more effective way to fabricate aAPC, encapsulating nanosystems with the natural cell membranes expressing these biological signals is capable of transferring mostly proteins to the surface of nanosystems for inducing tumor-specific CTLs.

Nearly ubiquitous, MHCI enables internal immune surveillance across cell types. By genetically modifying tumor cells to express co-stimulatory markers in conjunction with their naturally occurring MHCI on the cell surface, these tumors can present their own antigens in an immunostimulatory manner, enhancing immune recognition.²⁶¹ This approach offers a direct strategy to stimulate T cells specifically targeting tumors. Moreover, another innovative strategy involves fusing DCs with tumor cells, harnessing the combined power of abundant tumor-specific antigens, costimulatory molecules derived from DCs, and their efficient antigen processing and presentation machinery.²⁶² Recognizing the pivotal role of the fusion cell membrane, which encapsulates comprehensive tumor antigens and costimulatory molecules in enhancing immunotherapy efficacy, researchers have devised biomimetic nanosystems. These systems effectively trigger the activation of CTLs, thereby facilitating tumor cell elimination.^263,264 Ma and co-workers²⁶⁵ coated PLGA nanoparticles with cell membranes isolated from cells prepared by fusing DC and murine colon adenocarcinoma MC38 to synthesize the DC-MC38 fusion cell membrane-coated NPs (DMNPs). Endowed with antigen-presenting and costimulatory molecules on their membrane, DMNPs adeptly traverse lymphoid organs, stimulating T cells to elicit potent tumor-killing responses.

Analogously, antigen-primed DCs exhibit heightened expression of co-stimulatory molecules and MHCI molecules loaded with peptide epitopes. Consequently, DC membrane-cloaked biomimetic nanosystems are anticipated to mirror the antigen-presenting prowess of DCs, thereby activating T cells and eliciting robust antitumor responses. Chen et al.²⁶⁶ prepared BNs by cascade cell membrane coating. To elaborate, DCs were first exposed to nanoparticles coated with tumor cell membranes. Following this pre-pulsing, the DC cell membrane, adorned with relevant antigen epitopes, was harvested and subsequently utilized to encapsulate PLGA nanoparticles. BNs with multiple DC-associated membrane molecules had the capacity to directly cross-prime T cells and boost antigen-specific antitumor response (Figure 5A). In addition to the above examples, in the study of Cheng et al.,²⁶⁷ a “mini DC” is conducted by coating IL-2 loaded PLGA nanoparticles with cell membranes separated from tumor cell lysate-pulsed mature DCs. This biomimetic nanovaccine showcases the functional plasma membrane proteins of DCs on its surface, while concurrently releasing interleukin-2 (IL-2) in a paracrine fashion. This synergistic combination potently stimulates T cell activation and triggers a robust antitumor immune response. To further promote the interaction with T cells, Xiao and co-workers¹⁰⁵ encapsulated imiquimod-loaded PLGA with azido-labeled mature DC membrane, and used click chemistry to modify the surface with anti-CD3ε antibodies (αCD3ε), ultimately constructed nanoscale APCs, M^(αCD3ε/Ag)-NP-Imq. Hence, the αCD3ε could enhance interaction between nanoscale aAPCs and T cells with high expression of CD3 receptors, as well as accumulation and retention of aAPCs in LNs. M^(αCD3ε/Ag)-NP-Imq functions as an innovative aAPC, adept at activating and expanding T cell populations. Furthermore, it stimulates resident APCs to elicit potent antitumor immunity, offering a versatile and promising approach to tumor eradication (Figure 5B). In the study of Liu et al.,²⁶⁸ they crafted a genetically engineered cell membrane nanovaccine, ASPIRE, harnessing DCs infected with a recombinant adenovirus. This innovative platform integrates specific peptide-loaded major histocompatibility complex class I, anti-PD1 antibodies, and B7 co-stimulatory molecules, offering a tailored approach to immune activation (Figure 5C). ASPIRE nanovaccines potently evoke T cell responses by presenting targeted antigenic epitopes via MHC-I molecules. Additionally, they counter immunosuppression through the concerted efforts of B7 co-stimulatory molecules and anti-PD-1 antibodies, fostering enduring and potent CD8⁺ CTL responses.

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Furthermore, the versatile aAPC serves as a pioneering approach to bolster the stimulation and expansion of T cells ex vivo, ultimately enhancing the efficacy of adoptive T cell transfer therapies. In the study of Zhang et al.,²⁶⁹ MNCs, endowed with robust superparamagnetism and swift magnetic responsiveness, were enveloped with azide-functionalized leukocyte membrane fragments (LMNCs), yielding LMNCs. Subsequently, dibenzocyclooctyne (DBCO)-modified T cell stimuli were seamlessly attached to LMNCs through copper-free click chemistry, culminating in the fabrication of multifaceted aAPCs. The notable tumor growth inhibition, coupled with minimal side effects, underscores the promising potential of the aAPC platform in T cell-mediated anticancer immunotherapy.

Inhibiting exhaustion of T cells

Immune responses are commonly divided into two phases: the activation phase and the termination phase. When the exogenous antigens invade, the effective pathogen response of the immune system will be provoked. In that case, a large amount of T cells are activated to deal with that. In order to protect the T cells from extinction due to activation induced cell death under conditions of prolonged antigenic stimulation, the activated T cells will enter a state of exhasution through the negative regulators. These negative regulators are widely known as “checkpoints,” which are usually upregulated on the activated T cells, including CTLA-4 and PD-1.^270,271 However, to evade immune surveillance, tumor cells express several co-inhibitory ligands such as PD-L1. When PD-1 is engaged by PD-L1, activated T cells will be forced into exhaustion.¹⁰⁴ Against this background, ICB therapy was used to block negatively regulating immune checkpoints for inhibiting the exhaustion of CTLs.

ICB targeting the PD-1/PD-L1 pathway has performed remarkable clinical outcomes in various types of cancers. Combining with biomimetic nanosystems, various strategies have been developed to block the PD-1/PD-L1 immune inhibitory axis for enhancing tumor-specific T cell responses and inhibiting tumor progression. Due to the abundant expression of functional proteins, T cell membrane-coated nanosystems could be exerted for cancer immunotherapy. Kang and co-workers⁹⁰ prepared a BN (TCMNP) by encapsulating antitumor drug-loaded PLGA nanoparticles with the T cell membrane of the EL4 cell line which expresses various plasma-membrane proteins (Figure 6A). These T cell membrane-derived proteins conferred diverse properties to TCMNP. Specifically, adhesion proteins could mediate tumor targeting of the nanosystems, FasL played the role of tumor killing, PD-1 proteins were able to block immune checkpoint interactions, and TGF-β1R proteins could scavenge immunosuppressive molecules. Accordingly, TCMNP was capable of eradicating tumors through similar mechanisms as TCLs and overcoming the barriers of the immunosuppressive TME. What's more, cell membrane-derived nanovesicles can be engineered to express PD-1 receptors, in combination with other therapeutics to provoke antitumor immune responses. In the study of Zhang et al.,²⁷² 1-methyl-tryptophan (1-MT), a small molecule inhibitor of IDO, was encapsulated into PD-1 expressed cell membrane-derived nanovesicles to enhance the immune response against melanoma tumors. Zhai et al.²⁷³ also devised an innovative epigenetic nanoinducer, OPEN, cloaked in T lymphocyte membranes. This system enhances local interferon (IFN) production while inhibiting immune checkpoints. The core, which disintegrates upon glutathione (GSH) exposure, is crafted from bovine serum albumin cross-linked with a reversible linker (NHS-SS-NHS) and incorporates the LSD1 inhibitor ORY-100. The T lymphocyte membrane is sourced from IL-2-activated CTLs with PD-1 overexpression. Notably, OPEN-based therapy surpasses anti-PD-L1 therapy in antitumor efficacy across various mouse models (Figure 6B).

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In addition to PD-1 and CTLA-4, the T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is another inhibitory receptor found on lymphocytes.²⁷⁴ Tumor cells can inhibit the immune system and achieve immune escape by binding to TIGIT via CD155, which is widely expressed on their surface. In the study of Yu et al.,²⁷⁵ they constructed nanovesicles called O-TPNVs by loading oxaliplatin (OXA) using fusion membranes of TIGIT-expressing cells and platelet membranes. Based on previous studies, they found that OXA treatment upregulated CD155 expression of tumor cells, which could synergize with CD155/TIGIT blockade therapy for better therapeutic effects. Thus, after intravenously injected O-TPNVs, platelet membrane components could target postoperative wound and circulating tumor cells. Subsequently, OXA killed tumor cells and induced CD155 overexpression. At the same time, O-TPNVs blocked the CD155/TIGIT pathway and restored tumor-infiltrating CD8 T cells from the depleted state.

Notably, tumor cells upregulated the expression of PD-L1 to inhibit naïve T cell activation and effector T cell function.²⁵⁰ On account of the inactivation of T cells could seriously affect the antitumor efficiency of immunotherapy. ICB strategy such as anti-PD-L1 antibody is commonly used in combination therapy with BNCMs. Immune checkpoint inhibitors and biomimetic nanosystems tend to exhibit synergistic effects, substantially promoting the antitumor efficiency of immunotherapy based on CTLs.

Modulating the immunosuppressive TME

The eradication of highly immunogenic clones, coupled with the development of diverse immune evasion tactics, ultimately disrupts normal immune regulation, fostering the establishment of an immunosuppressive TME.²⁷⁶ The presence of immunosuppressive cells, including TAMs, Tregs, and MDSCs, and their associated cytokines (IDO, IL-6, galectins), constitutes a major barrier to effective immunotherapy. These factors collaborate to dampen tumor-specific T cell function, rendering cancers more resilient to immune-based therapies. Consequently, modulating the immunosuppressive TME to rejuvenate antitumor immunity has emerged as a crucial strategy for achieving successful immunotherapy against cancer.²⁷⁰

Macrophages, pivotal innate immune cells, originate from bone marrow-derived mononuclear precursors. They circulate in the bloodstream in an immature state, ultimately migrating to specific tissues to mature and fulfill their functions. Exposure to various cytokines, monocytes will differentiate and polarize into two types of cells with opposite functions, inflammatory M1-type macrophages, and anti-inflammatory M2-type macrophages. More details, IFN-γ, LPS, CSF-1, and other active molecules produced by microbes can promote the formation of M1-type macrophages, while differentiation of monocytes into M2-type macrophages are activated by IL-4, IL-3, and immune-suppressive agents.²⁷⁷ M1-type macrophages bolster immune defenses against pathogens and tumor eradication, driving robust immune responses. In contrast, M2-type macrophages downregulate immune response and facilitate immune invasion of tumors by secreting inhibitory cytokines. TAMs refer to the myeloid-derived macrophages and tissue-resident macrophages presented in TME.²⁷⁷ Anti-tumor M1-type macrophages are initially recruited, however, as the tumor progresses, they are gradually differentiated into M2-type macrophages which assist in the neovascularization, growth, invasion, and metastasis of tumors.²⁷⁸ As a consequence, repolarizing TAMs from M2-type to M1-type has emerged as a novel research direction.

Since the BNCMs absorb the remarkable capability of various proteins, certain BNCMs are able to enhance pro-inflammatory M1-type macrophage polarization. CSF-1R on macrophage membrane coated-nanosystems could deplete CSF-1 secreted by tumors, and thereby increase TAM polarization to the immune-promoted phenotype.^{85,86,279,280} Given that neutrophils do not aggregate systemically, neutrophil membrane-cloaked nanosystems hinder their infiltration into tumors. This mitigates the shift from antitumorigenic M1-type to immunosuppressive M2-type macrophage polarization mediated by neutrophil gelatinase-associated lipocalin.⁶² Besides, the NK cell membrane-coated nanosystems can interact with macrophage surface receptors, and thus promote M1-type macrophage polarization.⁹⁷ Moreover, OMVs were demonstrated to induce highly beneficial M2-to-M1 polarization of macrophages.¹⁷⁴ As reported in the study of Qing et al.,²⁸¹ calcium phosphate (CaP) pH-sensitive nanoshells were employed to cover the surface of OMVs prepared from Escherichia coli BL21 cells to prepare OMV@CaPs platform (Figure 7A). Different molecules in the OMVs reprogrammed the immune cell contents of the TME and conferred significant inhibitory effects against tumor growth. Meanwhile, to block serious inflammatory responses caused by OMVs, highly biocompatible CaP was introduced as the “shielding” shell. The successful implementation of FA modification and ICG loading strategies underscores the versatility of OMV@CaP as a robust platform, poised to explore diverse therapeutic combinations with great potential.

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Fibroblasts associated with cancer are termed CAFs, or tumor-associated fibroblasts. CAFs have cemented themselves as the vital component of tumor initiation, progression, and metastasis. They can remodel the ECM during the desmoplastic reaction by synthesizing various types of matricellular protein to constitute the ECM and basement membrane and producing metalloproteinase to maintain ECM homeostasis.^282,283 Meanwhile, CAFs are metabolically reprogrammed by tumor cells. Lactate, pyruvate, and ketone bodies produced by CAFs through aerobic glycolysis enter the tricarboxylic acid cycle of tumor cells to yield adenosine ATP, which supplies the energy required for tumor growth. A common strategy of targeting CAFs in cancer therapy involves depletion of CAFs, inhibition of CAF activation, halting infiltration of CAFs, reprogramming CAFs, etc. As shown in Figure 7B, Zang and co-workers²⁸² crafted a hybrid cell membrane by merging breast tumor (4T1) and activated fibroblast (3T3) membranes. This membrane encapsulated chemotherapeutic PTX and glycolysis inhibitor PFK15-laden solid lipid nanoparticles, yielding a biomimetic nanosystem (PTX/PFK15-SLN@(4T1-3T3) NPs). This dual-targeting design targets both tumor cells and CAFs. By inhibiting CAF glycolysis, we severed the supply of glycolytic metabolites to tumor cells. Additionally, decreased lactate secretion bolstered immune cell function, reversing the immunosuppressive TME and potentially inhibiting tumor growth.

The diverse pro-inflammatory cytokines present in the TME attract immature myeloid cells (IMCs), disrupting their maturation process. These IMCs, morphologically resembling monocytes or granulocytes, are collectively termed MDSCs. Murine MDSC subsets can be further classified into monocytic MDSCs (CD11bLy6C^+hiLy6G) and polymorphonuclear MDSCs (CD11bLy6C^+loLy6G). Through a diverse range of mechanisms, activated MDSCs are able to facilitate angiogenesis, immunosuppression, and tumor progression. TGF β, IL-10, IDO, etc. secreted by MDSCs have the potential to inhibit CD4⁺, CD8⁺ T cells, DCs, NK cells and promote differentiation of Treg cells. Meanwhile, MDSCs could down-regulate STAT-3 and increase HIF1α for leading the polarization of M2-type macrophages.^270,284 What's more, in the study of Li et al.,⁶³ they formulated innovative nanoplatform pCSs by wrapping around the PLGA nanoparticles with neutrophil MVs (Figure 7C). Owing to most membrane receptors inherited from neutrophils which were similar to polymorphonuclear MDSCs both in phenotype and morphology, pCSs played the role of nanodecoys, absorbing and neutralizing the growth factors and mediates that mediate expansion and tumor trafficking of MDSCs.

Overall, BNCMs inhibit the great potential to initiate or reinitiate cancer-immunity cycle for improving cancer immunotherapy. The summary of these biomimetic approaches is shown in Table 1.

Table 1 Summary of biomimetic nanosystems based on cell membranes to initiate or reinitiate cancer-immunity cycle for cancer immunotherapy.

Way to initiate cancer-immunity cycle	Source cell	Mechanisms of cell membrane	Inner cores	Refs.
Promoting TAAs release through chemotherapy	Erythrocyte	Evading immune clearance and prolonging systemic circulation	ZIF-8-DOX-LY-RM	[208]
	Leukemia cell	Targeting tumors	HMD	[209]
	Melanoma cell	Targeting tumors and evading immune clearance	GCT nanoparticle	[210]
Promoting TAAs release through radiation therapy	4T1 tumor cell and Escherichia coli	Stimulating the maturation of DCs and activating T cells	MGTe	[153]
	Mycobacterium smegmatis	Enhancing antigen uptake and stimulating the immune response	PC7A/CpG	[213]
Promoting TAAs release through photothermal therapy	Melanoma cell and Salmonella	Stimulating the maturation of DCs and serving as an immunoadjuvant	ICG-loaded PLGA	[223]
	4T1 tumor cell	Targeting tumors	AIEgens	[211]
Promoting TAAs release through photodynamic therapy	Plant-derived thylakoid and Escherichia coli	Serving as photosensitizers and immunoadjuvant	–	[230]
	Dendritic cell	Targeting and activating T cells	AIEgens	[231]
Promoting TAAs release through other therapies	Macrophage cell	Evading immune clearance and prolonging systemic circulation	HB-NLG8189	[230]
	CT-26 cell	Targeting tumors	Ag2S@P	[231]
	PD-1 antibody-anchored leukocyte	Prolonging systemic circulation and creating an immunogenic microenvironment	NC	[164]
	Leukemia cell	Targeting tumors and prolonging systemic circulation	GA/PLGA	[233]
Promoting TAAs release through combination therapies	ICG anchored 4T1 tumor cell	Achieving tumor accumulation	AuNC-PO2-Hb	[212]
	M1 macrophage	Targeting tumors	MPNP	[236]
	Anti-DEC205 engineered Hep1-6 cell	Targeting tumors, stimulating the maturation of DCs, and enhancing T cell priming	MOF@AuPt	[237]
Increasing APCs presentation	HNSCC patient derived tumor cell	Targeting tumors and stimulating the maturation of DCs	GNPs@Pt	[241]
	Tumor cell	Targeting resident DCs and macrophages and stimulating the activation of DCs	Neoantigen-loaded PLGA	[243]
	B16F10 tumor cell	Targeting tumors and stimulating the maturation of DCs	APC	[125]
	Irradiated tumor cell	Stimulating the maturation of DCs	PLGA-R837	[248]
	CD40 agonistic-antibody-anchored tumor cell	Facilitating the maturation of DCs and improving the engagement and expansion of cognate T cell immune responses	PLGA	[251]
	Tumor cell and Mycobacterium phlei	Providing tumor antigens and activating DCs	–	[256]
	Tumor cell and Escherichia coli	Stimulating the maturation of DCs and serving as immunoadjuvant	PLGA	[252]
	Bacteria	Displaying antigens and serving as immunoadjuvant	–	[253, 257]
Regulating T cells (enhancing activation of T cells)	Fusion cells of dendritic cell and tumor cell	Penetrating immune organs and activating T cells	CpG-loaded nanoparticle	[265]
	Dendritic cell	Cross-priming T cells and provoking robust antigen-specific antitumor responses	PLGA	[266]
	Dendritic cell	Provoking the activation and proliferation of T cells and triggering the antitumor immune response	IL-2 loaded PLGA	[267]
	anti-CD3ε antibody-linked dendritic cell	Targeting T cells and provoking the activation of T cells	Imiquimod loaded PLGA	[105]
	major histocompatibility complex class I, anti-PD1 antibody and B7 co-stimulatory molecules anchored dendritic cell	Improving antigen delivery to lymphoid organs and generating broad-spectrum T cell responses	–	[268]
	Anti-CD28 and pMHC-Ⅰlinked leukocyte	Provoking the activation of T cells	Magnetic nanocluster	[269]
Regulating T cells (inhibiting exhaustion of T cells)	T cell	Disrupting PD-1/PD-L1 immunosuppressive signals and scavenging immunosuppressive molecules	PLGA	[90]
	PD-1 overexpressed T cell	Disrupting PD-1/PD-L1 immunosuppressive signals and inhibiting exhaustion of T cells	ORY-1001-loaded BSA core	[273]
	TIGHT expressing cell and platelet	Targeting postsurgery wounds and circulating tumor cell and restoring CD8+ T cell activity	OXA	[275]
Modulating the immunosuppressive TME	Bacterial	Modulating the immunosuppressive TAM	–	[281]
	CAFs and tumor cell	Targeting CAFs	PTX/PFK15-SLN	[282]
	Neutrophil	Enabling the neutralization of MDSC-related cytokines and inhibiting the expansion of MDSCs	PLGA	[63]

CONCLUSION AND PROSPECT

In this review, we emphasized the BNCMs and their application for cancer immunotherapy. Although, immunotherapy has been in vogue for decades due to its clinical successes using ICI and CAR T cell therapy, the worries about low response rate and adverse events hindered its further application. Therefore, nanosystems with the capacities of high delivery efficiency and better safety have been explored to overcome the barriers of conventional immunotherapy. Nevertheless, the circulation time and stability of nanosystems remain to be improved by a biocompatible and reliable approach. Benefiting from the abundant functional molecules on the cell membrane, the biomimetic strategy based on the cell membrane mimics the unique properties possessed by source cells, such as excellent biocompatibility, low immunogenicity, and specific targeting ability. These biomimetic nanosystems are capable of efficiently delivering drugs to the lesion and facilitating the cancer immunity cycle for better immunotherapy with less off-target toxicities.

BNCMs derived from different source cells are discussed, mainly including erythrocytes, platelets, neutrophils, macrophages, T cells, NK cells, DCs, tumor cells, and bacteria. Erythrocyte membranes hold the “don't eat me” marker—CD47, achieving immune evasion and long-term systemic circulation. In addition to being able to cloak BNCMs, platelet membranes could target tumors via P-selection. As the most abundant component of white blood cells, neutrophils membranes are capable of targeting tumors and remodeling the immunosuppressive TME.⁶³ Meanwhile, various proteins expressed on the macrophage membranes mediated the targeting of primary and metastatic tumors. Besides, PD-1 on the T cell membrane could serve as a decoy to deplete PD-L1 in TME. NK cell membranes contain a series of molecules related to the elimination of tumor cells. DC membranes inherit the ability to target lymph nodes, present antigens, and prime T cells. What's more, TAAs and PAMPs on tumor cell membranes and bacterial membranes, respectively, facilitate antitumor immune response. In addition to those mentioned above, cell membranes of different origins or liposome membranes are fused to fabricate hybrid cell membranes with superimposed functions for performing increasingly complex tasks in dynamic TME. Furthermore, more functional molecules can be introduced to the surface of the cell membrane by being chemically modified and genetically engineered to achieve more functions. Diverse therapeutic inner cores encapsulated by cell membranes with suitable capabilities can participate in a certain stage of the cancer-immunity cycle, which mainly contained promoting the TAAs release from tumor cells, increasing APCs presentation, regulating T cells, and modulating the immunosuppressive TME. Thus, initiating or reinitiating the suspended cancer-immunity cycle to boost antitumor response to eliminate tumors.

Over the past decades, researches about nanosystems based on cell membranes have emerged in an endless stream. In one respect, the inner cores have been expanded from traditional polymers to oncolytic adenovirus^285,286 and bacterial^287,288; in another respect, membranes originated from sub-cellular organelles (mitochondria, endoplasmic reticulum, etc.) have been employed to endow biomimetic nanosystems with more unique properties.^289–293 At the same time, certain mechanisms of biomimetic nanosystems have been revealed, paving the way for their rational design.^294–298 However, there are still many properties of BNCMs that are required to be explored. Notwithstanding the fact that BNCMs are currently well-researched on two-dimensional (2D) systems of immortalized cancer cell lines and mouse models, their function mechanisms in human disease models are barren. For a more realistic simulation of the patient's TME, the three-dimensional (3D) organ-on-chip platform can exploit to analyze and observe the dynamics of BNs, as well as tumor evolution.^299,300 At the same time, computational tools such as molecular dynamics or simulations can be employed to broaden the understanding of the interactions between nanoparticles and organisms. Consequently, ensuring the consistency of efficacy between research and clinical disease, and laying the foundation for clinical studies of BNCMs.

Considering the biological complexity of cell membranes and technical limitations, there is still a tough way left to industrial and clinical scalability. The primary concern is the issue of raw materials of cell membranes. The cell membranes of erythrocytes and platelets, which are present in large quantities in the blood, can be extracted from blood products that are approaching their expiry date, thereby saving costs. For certain cells with an immortalized phenotype, cell membranes are capable of obtaining by in vitro expansion. But for other cells that can only be extracted from issues, it is currently difficult to apply. Meanwhile, it's vital to ensure that these source cells are free of potential safety hazards, including bacteria, viruses, and so on. Next, the safety of the MVs is required to be ensured, the most crucial of which is immunogenicity from MHC mismatchies.¹⁸³ Since most patients will receive BNCMs prepared by allogenic cells, their immunogenicity may result in suboptimal efficacy and side effects. The adverse immunogenicity issues of blood cells can be resolved by matching blood groups. And for the more structurally complex latter, designing universal cell lines may be the potential solution.¹⁸⁴ An additional issue, the quality control of MVs from different batches. As various sources or generations of cells will lead to discrepancies in the protein content of cell membranes. Therefore, partly it is necessary to minimize such differences, and partly it is essential to establish a suitable evaluation method to check the consistency of protein composition.

After the isolation, on account of issues about production costs and product quality, appropriate encapsulation methods at an industrial level still need to be explored. Although laboratory-scale cell membrane encapsulation techniques (co-extrusion and sonication, etc.) are well established, scaling them up to industrial levels is still challenging. Fortunately, owing to the characteristics of precise control of fluid flow rates as well as the programmed mixing and encapsulation process of microfluidics devices, they are promising for industrial-scale production of BNCMs with high reproducibility. Another concern is that since the uncoated cell membranes are still present in these mixed systems after encapsulation, there is a serious need for a purification method to avoid the toxicity associated with free cell membranes. As for the controllable quality of BNCMs, establishing a suitable evaluation system to monitor the quality of intermediate and final products is a critical matter. For cell membrane coating, the emphasis is on the consistency of protein composition and content as well as the functional and structural integrity of key proteins.³⁰¹ For the whole product, consistent quality is ensured by physicochemical properties, stability, and potency et al. Of particular, since BNCMs are closer to biological agents, the issue of how to prevent the loss of biological functions during transport and storage remains to be discussed.³⁰² Besides, since all medicines are tailored to their clinical value, the vital aspect that is required to be taken into consideration is the indication for which the BNCMs possess the most outstanding efficacy far beyond that of the control drug.

AUTHOR CONTRIBUTIONS

Yixi Wang: conceptualized and wrote the manuscript. Xianzhou Huang: helped with the conceptualization of the manuscript. Qinjie Wu: provided supervision. Changyang Gong: provided supervision and funding acquisition. All authors participated in manuscript editing and read and approved the final version.

ACKNOWLEDGMENTS

Figure 1 is created with the help of . All of the figures are processed by Adobe Illustrator. This work was financially supported by the National Natural Science Foundation of China (32301173, 82172094, 22205151, and 32201148), Key Research and Development Program of Sichuan Province (2023YFS0153), Funds of Sichuan Province for Distinguished Young Scholar (2021JDJQ0037), National Natural Science Foundation of Sichuan Province (24NSFSC7801), the 73rd Batch of General Fellowship from China Postdoctoral Science Foundation (2023M732444), 2023 National Fund Program for Postdoctoral Researcher (GZB20230477), and the Postdoctoral Research Fund of West China Hospital, Sichuan University (2023HXBH050).

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT

Not applicable.

ETHICS STATEMENT

The authors declare that human ethics approval was not needed for this study.

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