Engineering dendritic cell biomimetic membrane as a delivery system for tumor targeted therapy

Abstract

Targeted immunotherapies make substantial strides in clinical cancer care due to their ability to counteract the tumor's capacity to suppress immune responses. Advances in biomimetic technology with minimally immunogenic and highly targeted, are addressing issues of targeted drug delivery and disrupting the tumor's immunosuppressive environment to trigger immune activation. Specifically, the use of dendritic cell (DC) membranes to coat nanoparticles ensures targeted delivery due to DC's unique ability to activate naive T cells, spotlighting their role in immunotherapy aimed at disrupting the tumor microenvironment. The potential of DC's biomimetic membrane to mediate immune activation and target tumors is gaining momentum, enhancing the effectiveness of cancer treatments in conjunction with other immune responses. This review delves into the methodologies behind crafting DC membranes and the fusion of dendritic and tumor cell membranes for encapsulating therapeutic nanoparticles. It explores their applications and recent advancements in combating cancer, offering an all-encompassing perspective on DC biomimetic nanosystems, immunotherapy driven by antigen presentation, and the collaborative efforts of drug delivery in chemotherapy and photodynamic therapies. Current evidence shows promise in augmenting combined therapeutic approaches for cancer treatment and holds translational potential for various cancer treatments in a clinical setting.

Graphical Abstract

Introduction

Cancer remains a leading cause of mortality worldwide, exhibiting a notably aggressive nature [1, 2]. Projections from the Global Cancer Observatory suggest a grim future, with an estimated 30 million individuals succumbing to the disease annually by the year 2030 [3]. Traditional treatment modalities-surgery, chemotherapy, radiotherapy, phototherapy, and their multimodal integration-continue to be the mainstay in oncological management [4]. However, these conventional approaches often grapple with challenges, including cytotoxicity, nonspecificity, the propensity to trigger multi-drug resistance, and the potential to hinder the proliferation of cancer stem-like cells [5]. The growing understanding of the immune system's pivotal role in tumor dynamics has steered the evolution of immunotherapy, now an integral and promising adjunct in cancer care. The therapeutic landscape was revolutionized with the introduction of the first commercially available cancer immunotherapy, interferon-alpha (IFN-α), sanctioned in 1986 for hair-cell leukemia [6]. Successive milestones were marked by the United States Food and Drug Administration's (U.S. FDA) endorsement of recombinant interleukin-2 (IL-2) for metastatic kidney cancer in 1992 and metastatic melanoma in 1998 [7]. Immunotherapy leverages the body's immune defenses to mount an anti-tumor response, thereby mitigating tumor evasion. This strategy encompasses immune checkpoint inhibitors (ICIs), oncolytic viruses, adoptive cell therapy, and cancer vaccines. For example, T cells are major tumor killer cells, and immune checkpoint proteins (involving PD-1 and CTLA4) can reduce the multiplication and effector function of T cells [8]. ICIs, particularly, have shown efficacy in a spectrum of cancers by counteracting the tumor-induced suppression of T cell activity, these include melanoma, renal cell carcinoma (RCC), lung cancer, and squamous cell carcinoma of the head and neck, among others [8]. Dual ICI therapy or combinations with other drugs have yielded impressive outcomes in clinical settings. For example, the FDA-approved combination of nivolumab and ipilimumab has demonstrated objective response rates exceeding 30% in various cancers, with some instances reporting success rates of up to 50%. In the realm of combined immunotherapy for melanoma [9], RCC [10], colorectal cancer (CRC) [11], (hepatocellular carcinoma) HCC, non-small cell lung cancer [12] efficacy has been noteworthy, with all therapies reporting an objective response rate (ORR) surpassing 30%, with certain cases achieving rates upward of 50% [13]. In the realm of advanced soft-tissue sarcomas (STS), a dual-phase 2 trial named PEMBROSARC was conducted, investigating the effects of Pembrolizumab in tandem with low-dose cyclophosphamide. The outcomes were promising, revealing a 40% non-progression rate (NPR) at the six-month benchmark, alongside an ORR of 30% [14].

Dendritic cells (DCs) are pivotal antigen-presenting cells (APCs) that orchestrate the anti-tumor T cell response through various mechanisms. These include the migration of tumor-infiltrating DCs (TIDCs) to lymph nodes to present antigens to CD8⁺T naïve cells [15], and the recruitment of CXCR3⁺cytotoxic T lymphocytes (CTLs) to the tumor microenvironment (TME) via conventional type 1 dendritic cells (cDC1)-derived chemokines CXCL9/CXCL10 [16, 17]. The secretion of interleukin-12 (IL-12) and type I interferons (IFN-I) by DCs modulates CTL functionality within the TME [18–20]. T cells eradicate tumor cells predominantly through two mechanisms: degranulation, which involves the release of perforin and granzymes to induce tumor cell lysis, and the Fas/FasL pathway, triggering apoptosis in tumor cells. Beyond direct cytotoxicity, DCs facilitate the differentiation of CD4⁺T cells into specialized effector subsets [21] and activate B cells [22] for antibody-mediated responses, as well as natural killer (NK) cells via IL-12, interleukin-15 (IL-15), and IFN- I [23]. It is in multiple pathways of both primitive and adaptive immune responses that DCs play important immune role [24]. Leveraging DCs' innate immune capabilities for cancer immunotherapy has shown promise, evidenced by the FDA-approved dendritic cell-based vaccine for prostate cancer [25]. Novel strategies, such as RNA-lipid complexes (RNA-LPX) that target DCs, have been developed to enhance antigen uptake, expression, and subsequent INF-α release [26]. The broad applicability of RNA-LPX, capable of encoding various polypeptides, underscores the potential of DC-targeted therapies. Despite the therapeutic potential, the clinical implementation of cancer immunotherapy is hampered by adverse effects, including autoimmunity and nonspecific inflammatory responses, compounded by the absence of precision delivery systems [27]. Research is advancing towards novel delivery platforms, such as nanoparticles and biomaterials, to mitigate these challenges [27].

Cell-based immunotherapies are at the vanguard of current research, with cell membrane-coated nanotechnology gaining traction. Nanoparticles, inherently small and often biodegradable, are utilized for their superior tissue penetration and delivery of immune adjuvants [28]. Utilizing cell membranes directly harvested from natural sources, these nanoparticles can be optimized for biocompatibility and targeted drug delivery [29]. Cell membrane-coated nanoparticles (NPs) have been investigated in oncology for their drug carriage and targeting enhancement properties [30, 31]. Recent studies have applied this technology to nanosuspensions, aiming to increase drug concentration at targeted sites [32, 33]. The biomimetic nanoformulations derived from various cell membranes inherit properties of the source cells, enabling them to navigate complex biological environments effectively [34]. The cell membrane-based drug delivery systems exhibit functionalities akin to the native cells due to the presence of specific proteins, glycolipids, and glycoproteins, thus offering a mimetic approach to drug delivery. The biomimetic approach benefits from its ability to evade the immune system, ensure prolonged circulation, provide high specificity and targeting, exhibit low cytotoxicity, and maintain strong biocompatibility with the added advantage of facile degradation [1, 35, 36]. Cell membrane-derived materials may originate from various natural cells, including erythrocytes [37], leucocytes [38], platelets [39], cancer cells [40], macrophages [41], mesenchymal cells [42], or a combination thereof, each with distinct properties tailored to treat specific diseases [43]. Moreover, different receptors on the same cell membrane can be exploited to treat various diseases. For instance, platelet research, which spans tumor, cardiovascular, infectious, and immune diseases, is well-documented [44]. Since multiple immune cells are involved in the immune response to a disease, immunotherapies based on various cell membranes can target the same pathology. Leukolike vectors (LLVs), for example, have proven effective in tumor targeting by actively and nondestructively binding to cancer endothelial cells for drug delivery [38]. Hybrid bionic membranes, created from mouse ID8 ovarian cancer cell and erythrocyte membranes, have been engineered for ovarian cancer therapy with a formulation known as Fe3O4-ICG@IRM, consisting of indocyanine green (ICG) encapsulated within the hybrid membrane [43]. Crucial APCs, particularly DCs, exhibit superior migration and T-cell activation capabilities.

Tumor-associated antigens (TAAs) are processed by APCs and presented to CD4⁺T cells via MHC-II molecules, while also being cross-presented to CD8⁺T cells through MHC-I molecules, triggering their activation. This complex process is vital to antitumor immunity, emphasizing its pivotal role in mounting a robust response against cancer cells [45, 46]. The antigenicity of tumor cells forms the foundation of cancer immunotherapy [47]. Recent experiments utilizing DC biomimetic membrane delivery for cancer immunotherapy have shown significant progress in treating diseases such as breast cancer [48], ovarian cancer [32] and so on.

This manuscript offers a detailed analysis of the recent advancements in nanoparticulate drug delivery systems utilizing DC biomimetic membranes for precision-targeted cancer therapeutics through immunomodulation. It begins by elucidating the pathological involvement of DCs in tumor immune responses, followed by an examination of the synthetic strategies and characteristics of these biomimetic nanocarriers. The discussion extends to the clinical applications of DC membrane-coated biomimetic nanoparticles in managing malignancies such as breast cancer, ovarian cancer, and neuroglioma. The conclusion highlights the obstacles and prospective directions for employing DC-based biomimetic nanotechnologies in cancer-specific treatments.

Dendritic cells and cancer

The discovery of DCs in the mouse spleen by Steinman RM et al. in 1973 marked the identification of a novel cell type [49], leading to subsequent research in the 1970s that highlighted the robust capability of DCs to activate cytotoxic T lymphocytes [50]. In recognition of these seminal findings, Ralph Steinman was posthumously awarded the Nobel Prize in Medicine or Physiology in 2011 [24]. DCs are involved in various types of cancer through multiple mechanisms (Fig. 1). DCs primarily act in concert with other immune cells to modulate tumor behavior. Once mature, DCs stimulated by TAAs enhance the proliferation and activation of T lymphocytes, utilizing co-stimulatory molecules (CD80 and CD86) and antigen-presenting molecules (MHC-I and MHC-II) to transmit signals through interactions with T-cell receptors (TCR) and CD28 on T cells, thereby encouraging the replication and activation of both CD8⁺ and CD4⁺T cells [28, 32, 51]. Activated CD8⁺T cells, or CTLs, specifically target and induce apoptosis in tumor cells [52]. CD4⁺T cells predominantly amplify CTLs anti-tumor activity through immune regulation but have also been found to possess direct cytotoxic capabilities in both preclinical and clinical studies, with cytotoxic CD4⁺T cells identified in human cancer research [53–55].

Fig. 1.

Dendritic cells in Cancer. DCs play a multifaceted role in various cancers, including melanoma, breast cancer, and ovarian cancer. In particular, dendritic cells play a crucial role in initiating and regulating immune responses. They capture, process, and present antigens, which subsequently activate T cells to foster an anti-tumor immune response. Additionally, they regulate immune responses through the secretion of cytokines and chemokines. However, cancer cells can employ various mechanisms to disrupt dendritic cell function, allowing tumors to evade immune surveillance. This disruption induces tumor immune tolerance and promotes tumor growth

Under inflammatory conditions, marked by the expression of the transcription factor Nur77 and mediated by the chemokine receptor 2 (CCR2) pathway [56–60], common myeloid progenitors (CMPs) give rise to monocytes, which subsequently differentiate into monocyte-derived DCs (moDCs). Conversely, in the absence of Nur77, CMPs give rise to macrophage DC progenitors (MDPs) and then to the common DC precursors (CDPs) [56, 57], which further differentiates into CD123⁺CD11c⁻plasmacytoid dendritic cells (pDCs) and CD123⁻CD11c⁺conventional dendritic cells (cDCs) (Fig. 2) [57, 61]. DCs exhibit significant diversity in function and phenotype. The terminology used to describe these diverse subsets has evolved over time, and advancements in flow cytometric techniques and genomic profiling methods have enhanced our understanding of human DC heterogeneity of selected lineages. Both mice and humans have equivalent populations for each subset (Table 1). cDCs, also identified as Lin⁻CD135⁺MHCII⁻CD11c⁺DCs [62, 63], are further classified based on transcription factor profiles, surface markers, and functional properties into the cDC1s and conventional type 2 DC (cDC2) subgroups [25, 57]. cDC1s, characterized by surface markers such as HLADR⁺CD11c⁺CD123⁻CD11b⁻Sirpα⁺CD141⁺Clec9A⁺, [64–69] produce chemokines CXCL9 and CXCL10 that recruit tumor-specific T cells to the tumor milieu [24]. cDC1s are primarily found in nonlymphoid tissues [64–69] and are known for their superior ability to cross-present antigens and activate cytotoxic T cell responses [70]. cDC2s, marked by HLADR⁺CD11c^hiCD123⁻Sirpα⁺CD1c⁺Clec9A⁻, [64, 71–73] are present in both lymphoid and nonlymphoid tissues [64, 74] and are less efficient in cross-presentation compared to cDC1s.[64, 75]Upon activation, cDC2s can release a range of cytokines, including IL-12 and tumor necrosis factor-α (TNF-α) [70].

Fig. 2.

Dendritic cell differentiation. Hematopoietic stem cells (HSC) differentiate into common lymphoid progenitors (CLP) and common myeloid progenitors (CMP) which contribute to the generation of monocyte and macrophage DC progenitor (MDP). Monocytesand MDP can further give rise to monocyte DCs (moDCs). The conventional type 1 DC (cDC1), conventional type 2 DC (cDC2), and plasmacytoid DC (pDC) subsets originate from the CDP, with each lineage influenced by different key transcription factors

Table 1.

Phenotypes of human dendritic cells and mice dendritic cells

DC subtype	Human cell surface markers	Mouse cell surface markers
cDC1	XCR1 CD45 CADM1 CLEC9A CD141 HLA-DR DEC205 BTLA CD26 DNAM-1/CD226 CADM1	CD8a (resident cDC1s) CD103 (migratory cDC1s) XCR1 CD24 CD11c MHC-II CLEC9A DEC205 XCR1 CADM1
cDC2	CD1c/BDCA-1 CD172a CD45 FceR1A CD11c CD11b CD2 SIRPA ILT1 CLEC4A/DCIR CLEC10A HLA-DR CD1a(migratory cDC2)	CD11b CD172a CD11c MHC-II SIRPA
pDC	CD123 CD303/CLEC4C/BDCA-2 CD304/NRP1/BDCA-4 CD45RA CD2 CCR2 CXCR3 FCER1 ILT3 ILT7 DR6 HLA-DR CD4 MHC-II	B220 SiglecH CD317 Ly6D Ly6C CCR9 CD172a CD209 CXCR3 BST2
moDC	CD11c CD1c/BDCA-4 CD1a SIRPA S100A8/A9 CD206 DC-SIGN/CD209 HLA-DR	MHCII CD11c CD11b CCR2 CD209

cDC1

In the tumor microenvironment, cDC1s are pivotal in capturing tumor-associated antigens (TAAs), presenting them to naïve T cells, and fostering CD8⁺cytotoxic T cell responses, a mechanism that has been harnessed in cancer immunotherapy [75]. DCs play a crucial role in tumor immunity by acquiring antigens, migrating to lymph nodes, and orchestrating the T-cell-mediated immune response (Fig. 3). The activation of DCs is marked by the translocation of MHC-peptide complexes to the plasma membrane, upregulation of chemokine receptor CCR7, adhesion molecules, and co-stimulatory molecules such as CD54, CD80, and CD86, alongside cytokine secretion that fosters cellular proliferation and differentiation. These processes are pivotal for initiating an immune response and facilitating antigen-bearing cell migration to lymphoid structures [24, 76]. DCs operate via a spectrum of receptor-mediated mechanisms, including Fc receptors (CD64 and CD32), integrins (αvβ3, αvβ5), C-type lectin receptors (e.g., mannose receptor, DEC205), receptors for apoptotic cells, scavenger receptors, and endocytic pathways for antigen internalization [24].

Fig. 3.

Mechanism of dendritic cells participating in anti-tumor immunity. DC originates from HSC in the bone marrow and differentiate into various subsets, such as cDC1, cDC2, moDC and pDC. cDC1 takes up tumor antigens and migrates through CCR7-dependent mechanisms to tdLN. And then, the tumor antigen is cross-presented to CD8⁺ T cells to activate anti-tumor immunity. cDC2 mainly act on the CD4⁺T cells, which plays a regulatory role in the cytotoxicity of CD8⁺ T cells. moDC works primarily under inflammatory conditions. pDCs act in a dual capacity in immune regulation of the tumor microenvironment. Different kinds of cells interact with each other through secretion of cytokines and various signaling pathways to participate in anti-tumor immunity

The functions of DCs vary in different locations such as tumors, lymph nodes and lymphatics, with cDC1s being the most representative example. In the tumor microenvironment, cancer cells themselves secrete CXCL1, CCL2, and CCL20 to attract tumor-promoting immune cells such as monocytes, macrophages, regulatory T cells (Treg cells), and T helper cells [77, 78]. cDC1s are recruited into the tumor microenvironment by chemokines such as XCL1 and CCL5 produced by natural killer (NK) cells and other possibly lymphocytes within the tumor [79]. NK cells further secrete the growth factor FLT3L, which supports cDC1 survival and may enhance differentiation of local cDC1s and DC precursors [80]. Within the tumor, cDC1s absorb antigens from tumor cells, and produces chemokine CXCL9/10, which can recruit CD8⁺ effector T cells into tumor tissues. In addition, cDC1s can locally present antigens to T cells recruited in the tumor microenvironment (TME) for activation or transport tumor antigens to tumor draining lymph nodes, and then present them to naive CD8⁺T cells, causing cytotoxic effects, and the activated CD8⁺T cells are transported to the tumor through the blood [77, 81]. The immune cells that make up the lymph node immune microenvironment include macrophages, dendritic cells, T cells, B cells, and non-immune cells such as fibroblast reticular cells (FRC), blood endothelial cells (BECs), and lymphatic endothelial cells (LECs) [82]. In the lobular structure, B cells and T cells interact with resident DCs of lymph nodes (LNs) and migratory DCs recruited from the periphery via afferent lymphatics [83, 84]. Lymphatic vessels (LVs) are crucial for DC transport from tumor tissue to the drainage LN and activation of the immune response [85]. Studies have shown that VEGF-C-induced lymphangiogenesis enhances DC transport to deep LNs (dLNs) [85]. One of the known dominant factors of DC migration is CCL21/CCR7 axis [86]. CCR7 is up-regulated in mature DCs, and its two ligand chemokines are CCL21 and CCL19 [87, 88].

cDC1s, identified in mice by CD103 expression, are unique APCs that robustly activate and expand CD8⁺T cells in vitro [89]. CD103⁺cDC1s are crucial for eliciting anti-tumor immunity and actively transport tumor-associated antigens (TAAs) to lymph nodes via CCR7-mediated migration [76, 90, 91]. Despite a subset of tumor-infiltrating DCs reaching the lymph nodes, likely modulated by CCR7 expression, mature DCs prominently express this chemokine receptor to navigate to lymphatic vessels and nodal tissue following the CCL21 gradient [91]. This CCR7/CCL19/CCL21 axis not only aids in DC and T cell recruitment to the TME and subsequent immune activation but also potentially facilitates metastatic spread of CCR7⁺cancer cells [75, 92–94]. Blood-derived cDCs and pDCs can also upregulate CCR7 in response to lymph node chemokine signals, enhancing their homing capacity [95]. The directivity of DC migration is mainly mediated by the gradient of soluble chemokines. In addition to the CCL21/CCR7 axis, other biomolecular molecules, such as C-type lectin receptor (CLEC-2), podoplanin (PDPN) and Sema3A, podoplanin, are thought to be involved in the adhesion and migration of lymphatic DCs [86]. Additionally, cDC1s secrete CXCL9 and CXCL10, which are instrumental in attracting tumor-specific CD8⁺T cells to the tumor site and promoting their cytotoxic function [96].

The generation of spontaneous anti-tumor immunity is contingent upon cDC activation by type I interferon (IFN-I) [25]. IFN-I signaling augments cDC1 activation, migration, and cross-presentation capabilities [56]. DCs in the TME can produce IFN-I via the STING pathway upon detecting tumor-derived DNA [97]. Research indicates that Batf3⁺DCs are proficient in antigen cross-presentation, with BATF3-dependent cDC1s requiring the type I interferon receptor (IFNAR1) expression for this function [98]. The anti-tumor response is substantially reliant on IFNAR1 [99, 100]. Immune checkpoint blockade with agents like aPD-1 triggers T cells to release interferon-γ (IFN-γ), which in turn stimulates DCs to produce IL-12, catalyzing anti-tumor T cell immunity [19]. The exact mechanism behind cDC1-mediated T cell response, potentially involving IL-12, remains to be elucidated. Lastly, activated CD8⁺T cells orchestrate the recruitment of pDCs and cDC1s through the CCL3/CCL4 and XCL1 chemokine pathways, respectively [101]. To encapsulate, the synergy between cDC1 and CD8⁺T lymphocytes is a pivotal mechanism in cancer pathogenesis, implying that disrupting their interaction could emerge as a viable strategy for oncological therapies.

Cytokines such as FMS-like tyrosine kinase 3 ligand (Flt3L) and granulocyte–macrophage colony-stimulating factor (GM-CSF) are known to foster DC differentiation and mobilization. In contrast, DC-expressed T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) suppresses the anti-neoplastic immune response, while cyclooxygenase-2 (COX-2) impedes DC maturation via the COX-2-PGE2 pathway [89]. Furthermore, agents like vascular endothelial growth factor (VEGF), prostaglandin E2, interleukin-10 (IL-10), interleukin-6 (IL-6), and colony-stimulating factor 1 (CSF-1) have been identified as inhibitors of DC activation and maturation [25, 102]. Notably, transforming growth factor-β (TGF-β) exhibits a bidirectional effect on oncogenesis [89]. Consequently, strategies to augment DC-mediated anti-tumor immunity within the TME and mitigate suppressive influences are of paramount importance.

cDC1s also crucially initiate CD4⁺T cell responses by transporting antigens to the lymph nodes, where cDC2s acquire and present these antigens to CD4⁺T cells. This interaction, facilitated by MHC Class II molecules leading to cDC1-specific CD40 signaling [103], is essential for the subsequent CD8⁺T cell response. CD8⁺CTLs are instrumental in tumor eradication, with CD4⁺T cells bolstering CTL proliferation and enhancing their tumoricidal activity [104, 105]. The enhancement of CD8⁺T cell function by CD4⁺T cells is primarily mediated through cytokines like IL-2 and interactions involving CD40 and CD40L [106, 107].

Furthermore, DCs regulate T cell activation and suppression chiefly through the interaction of membrane proteins CD80 and CD86 with their T cell counterparts CD28 and CTLA-4, respectively [108]. Additional co-stimulatory interactions include CD40-CD40L, CD137-CD137L, OX40-OX40L, GITR-GITRL, and CD70-CD27, all of which are integral to DC-mediated T cell activation and anti-tumor immunity [109].

cDC2

cDC2s account for a large proportion of the DCs population, but its functional properties are poorly understood [110]. Unlike cDC1s, which specifically express XCR1 and CLEC9A, CDC2-specific markers have not been identified, which increases the difficulty of specifically addressing the role of cDC2s in tumors [45]. cDC2s are not as high as the inhibitory receptors expressed by cDC1s (such as TIM3, BTLA, PD-L1) and migration-related receptors (such as CCR7 and Clec9a), suggesting that they have weaker dLN-bound migration potential than cDC1s [110]. Although both cDC1s and cDC2s in humans can produce IL-12 in response to toll-like receptor (TLR) stimulation, the levels of IL-12 in human cancer are primarily associated with increased infiltration of cDC1s [18, 111]. In contrast, cDC2s are not directly involved in activating CD8⁺T cells within tumors but are essential for initiating anti-tumor CD4⁺T cell responses [91, 112]. Studies have shown that when BATF3 is absent, cDC1s in the tumor are reduced, which led to increased cDC2 migration to lymph node and CD4⁺ T cell activation [110]. In a study, researchers have shown that cDC2 infiltration is more strongly associated with the survival of breast cancer patients than cDC1s, indicating that the genetic characteristics of DC subtypes have different prognostic values for different human tumors with different immune microenvironment [110]. cDC2s exhibit reduced expression of endocytic receptors, such as CD36 and Clec9a, which are crucial for apoptotic cell recognition. The augmented lysosomal enzyme activity and reduced phagosomal pH in cDC2s may lead to antigen degradation during migration [113, 114]. cDC2s have a function that other subtypes do not, namely the production of retinoic acid under the stimulation of vitamin D3, which stimulates CD4⁺ naive T cells to express intestinal homing molecules and produce Th2 cytokines [115]. Studies have linked cDC2 abundance with non-regulatory CD4⁺T cell infiltration in cancer, indicating that cDC2s present tumor antigens to CD4⁺T cells and migrate from the tumor to the lymph nodes, especially in the absence of regulatory T cells (Tregs), which can enhance CD4⁺T responses [116]. Moreover, migratory CD11b⁺cDC2s have been recognized as significant inducers of anti-tumor CD4⁺T cell initiation. cDC2s also promote the proliferation of naive CD4⁺T cells into T helper 1 (Th1), T helper 2 (Th2), and interleukin-17-producing T helper (Th17) subsets [117, 118].

moDC

Within an inflammatory milieu, monocytes are capable of maturation into various effector cell types such as inflammatory dendritic cells, particularly monocyte-derived DCs (moDCs) [25, 98]. Nonetheless, the distinction between some human cDC2s and moDCs is confounded due to overlapping marker expression, complicating their definitive identification [56, 119]. Furthermore, cells resembling "MoDCs" generated during inflammation are now commonly classified as highly plastic or "non-classical" monocytes rather than true DCs [59]. Therefore, further research is needed to better define these DC and monocyte subpopulations and their behaviors in different tissues and inflammatory environments, particularly in humans [109]. Although their crucial role in immune responses during inflammatory contexts is evident, the role of MoDCs in spontaneous anti-tumor immunity remains unclear [56]. However, their potential in mediating anti-tumor effects should not be dismissed. During inflammation, moDCs are implicated in the recruitment and secretion of TNF and nitric oxide synthetase (NOS2), influencing T cell activity within tumors, a characteristic of tumor necrosis factor-inducible DCs (TipDCs) [98, 120]. It has been elucidated that nitric oxide (NO) generated by certain myeloid cells infiltrating tumors is indispensable for the efficacy of anti-tumor CD8⁺T cells, with these cells exhibiting phenotypic similarities to TipDCs [121]. Furthermore, p53 activation in myeloid precursors fosters the emergence of CD103⁺moDCs, which are proficient in cross-presenting antigens to CD8⁺T cells and secreting IL-12 to bolster anti-tumor responses [122, 123]. Despite the emerging concept that all human DC subsets have the capability for cross-presentation, this ability is influenced by various factors such as the nature of the antigen. Although MoDCs possess the capacity for cross-presentation, they do so with low efficiency and are more adept at processing antigens through the vacuolar pathway instead of the cytosolic pathway [123]. In mice, while MoDCs also can produce IL-12 after immunogenic stimulation [124], IL-12 is primarily generated by cDC1s and involved in the initiation of Th1 cell and CD8⁺ T cell responses [125]. Predominantly arising from inflammatory responses, moDCs play a pivotal role in driving the differentiation of CD4⁺T cells into Th1, Th2, or Th17 cells [126].

pDC

pDCs, as identified since 2008, express major histocompatibility complex class II (MHC-II) molecules and costimulatory molecules [127], and are characterized as lineage-negative Lin⁻MHC-II⁺CD303⁺CD304⁺cells [24, 128]. They exhibit plasma cell-like morphology and express various markers including CD4, human leukocyte antigen-DR (HLA-DR), CD123, blood-derived dendritic cell antigen 2 (BDCA-2), and Toll-like receptors (TLR) 7 and 9, but not CD11c [129–131]. Residing primarily in the T-cell zones of lymphoid organs and present in blood and select peripheral tissues, their recruitment to tumor sites is often associated with poor prognostic outcomes [131–133].

The antigen-presenting capacity of pDCs remains ambiguous, with limited evidence suggesting a subsidiary role in this process [62, 134, 135]. Yet, bone marrow-derived pDCs have demonstrated antigen presentation capabilities, with their relevance to cancer contingent on their myeloid lineage and activation status [56, 135]. pDCs also migrate through the high endothelial venules of lymph nodes and the marginal zone of the spleen to reach the T-cell zone of secondary lymphoid tissues, probably via CCR7 and CD62-L [95]. After TLR7/9 triggering, pDCs release large amounts of INF-1 and produce proinflammatory chemokines, including interleukin-12 (IL-12), IL-6, and TNF-α [98, 130]. pDCs are usually involved in anti-tumor immunity by secreting IFN-1 and other inflammatory factors such as IL-6 and TNF-α [56, 98, 127]. In murine B16 melanoma, TLR agonist-stimulated pDCs are able to effectively induce tumor cell death by expressing TNF-related apoptosis-inducing ligand (TRAIL) and granzyme B and C. Additionally, they contribute to their antitumor effects by producing IFN-I, subsequently activating CTLs and NK cells [132, 133, 136]. Although pDCs of human and mouse can be stimulated to effectively initiate CD8⁺T cells, pDCs have a relatively poorer ability than cDCs to initiate naive T cells [58, 137].

Compared to classical DCs, the functions of pDCs are largely innate and limited to detecting viral infections and producing type I interferon [138]. Although type I interferons have been shown to have anti-tumor effects, the role of pDCs in tumor control remains controversial. In fact, with some exceptions, it is generally accepted that pDCs help to induce tolerance and promote tumors [45]. The presence of pDCs (CD123⁺BDCA2⁺) has been found in breast cancer tissues, and increased pDC frequency is associated with the aggressiveness of breast tumors [139]. Studies of for colorectal cancer [140], ovarian cancer [141], and head and neck cancer [142] have also reported poor tumor prognosis in the presence of high invasion of pDCs.

pDCs have a dual role in the tumor microenvironment, both initiating antitumor immunity by producing type I interferon and activating cytotoxic T lymphocytes and NK cells, and facilitating immune tolerance by expressing molecules such as indoleamine 2,3-dioxygenase (IDO) and programmed death-ligand 1 (PD-L1) [47, 143]. These cells can both stimulate CD8⁺T cell responses and promote regulatory T cell proliferation through various immunosuppressive pathways, including TGF-β, IL-10, and CTLA-4, which can lead to a decrease in cytotoxic T lymphocyte activity. The presence of pDCs in tumor-draining lymph nodes, expressing IDO, can modulate the local tryptophan catabolism, thereby affecting T cell proliferation and function and inducing immune tolerance [144–147]. Tryptophan catabolism byproducts directly toxify T lymphocytes [148, 149]. DCs promote regulatory T cell differentiation via IDO production [150, 151]. Notably, pDCs are co-opted by tumors within TME for immunosuppression [45], thereby diminishing CTL activity by fostering Treg cell proliferation [139, 152]. Furthermore, pDCs impede T cell proliferation through modalities such as TGF-β, IL-10, and CTLA-4 [153, 154]. Specifically, IL-10 production by type 1 T regulatory cells is enhanced by pDCs in hepatocellular carcinoma context, partially through an inducible T cell co-stimulator ligand (ICOSL) [155, 156], ICOSL expression on pDCs correlates with breast cancer progression via IL-10-producing Treg cells [98]. Additionally, PD-L1-expressing pDCs attenuate T cell responses by engaging with the PD-1 receptor on T cells [74]. Moreover, pDC recruitment by tumors leads to Treg cell expansion and reduced anti-tumor CTL presence [68]. A significant presence of pDCs expressing OX40L and ICOSL is linked to increased interleukin-5 (IL-5), IL-10, and interleukin-13 (IL-13) production by T cells in melanoma [98]. Therefore, strategic manipulation of pDCs could be a pivotal step in enhancing antitumor immune responses.

In different subtypes of DCs, the cDC1 subgroup is associated with inducing cancer-controlling immunity and increased survival for some cancer types. And during treatment with immunogenic cell death-inducing chemotherapy agents and radiation therapy MoDCs are fundamental [109, 157], while cDC2s are key to inducing anti-tumor CD4⁺ T cell immunity. However, despite the fact that naturally occurring human cDC1s is connected with a good prognosis, MoDCs have been used in most of the current research on DCs membranes as a delivery system for tumor targeted therapies [158–160]. Similar to the application of DCs to cancer vaccines, which also has the same situation, we speculate that this may be because of the low incidence of cDC1s in peripheral blood [109]. In the context of cancer, different subsets of DCs have unique functional immune responses. Overall, we need to learn more about how to optimally utilize specific subsets of DCs with specialized functions to coordinate an effective immune response against cancer [109].

Characterization of Dcs activation and aDCm@PLGA/DRUG preparation

Isolation of pure DCs membranes

The immunocytoplasmic membrane serves as a critical interface for cellular function, allowing for effective signal transduction and maintaining intracellular stability. This membrane's structural heterogeneity and functional optimization enable the evasion of immune detection, prolonging the systemic circulation of biomimetic nanoplatforms and facilitating targeted delivery to immune and tumor cells through specific molecular recognition [160]. Consequently, the immunocytoplasmic membrane can endow nanoparticles with superior biocompatibility and immune evasion capabilities [161, 162].

The generation of activated mature dendritic cells (aDCs) involves the culture of bone marrow-derived dendritic cells with whole tumor cell lysate (WTCL) or tumor membrane as a source of diverse antigens, in the presence of GM-CSF and interleukin-4 (IL-4) to enhance maturation [160, 163, 164]. Identifying tumor-specific antigens among a broad spectrum of tumor-associated antigens remains challenging; however, co-culturing with whole tumor plasma membrane antigens can simulate the natural immune response and potentially lead to more effective dendritic cell activation [165]. Incorporating the entire tumor antigen array mitigates the issue of reduced DC membrane targeting efficacy due to tumor heterogeneity [166] though the presence of non-tumor-associated antigens may diminish the rate of anti-tumor immune responses [167]. Optimal DCs activation and antigen presentation are achieved by fine-tuning the incubation period and concentration during the co-culture of immature DCs with tumor cell lysate (TCL) [163]. Furthermore, employing dendritic cell membranes induced by multiple antigens enhances target specificity, reduces the probability of immune evasion, and amplifies the immunogenic response. The assessment of mature DCs activation relies on three metrics [163]: (1) CD80/86 surface expression ascertained via flow cytometry; (2) the presence of peptide-major histocompatibility complex (pMHC) molecules; (3) the quantification of TCL-derived antigens on the DCs surface determined by gel electrophoresis. Following maturation, these dendritic cells can be subjected to membrane extraction for subsequent applications. Flow cytometry showed that DC was activated, indicating that the expression of aDC costimulatory molecule CD80 / 86 was higher than that of iDC, and the positive expression of pMHC was also higher. Gel electrophoresis showed that the composition of TLC protein appeared on aDC but not on iDC [163].

Current methodologies for cell membrane isolation share the unified principle of preserving membrane proteins and preventing component loss. APC membranes are procured through a sequence of freeze–thaw cycles, followed by low-temperature centrifugation to separate the disrupted membranes. These membranes can be lyophilized for storage and rehydrated in ultrapure water before application [51]. The antigen-presenting dendritic cell membrane (aDCm) preparation, involving freeze–thaw cycles, sonication, and resuspension, results in minimal protein loss. Additionally, aDCm can be obtained via ultrasonic disruption followed by ultracentrifugation, allowing for mass production while maintaining membrane functionality for subsequent experimental procedures [159, 163, 164]. Other cell disruption techniques include hypotonic lysis [32] and chemical lysis [168], with the addition of protease inhibitors to preserve protein integrity.

Preparation of Hybrid membrane

The cellular membrane's complexity is demonstrated by the presence of domains within the cancer cell membrane that facilitate adhesion to analogous cells and proteins [169]. Notably, activated mature DCs exhibit potent migratory capabilities to lymph nodes, paralleled by the homologous targeting potential of tumor cells. Hybrid membranes, encompassing components from mature DCs and tumor cells, show enhanced targeting of lymph nodes and tumors [28]. This duality not only empowers antigen-presenting cells but also endows coated nanoparticles with the ability to home in on cognate tumors, driving the exploration of hybrid cell membranes. The interplay between the cell membrane and its external environment underpins cellular function.

Co-cultivating dendritic cells with irradiated, inactivated tumor cells yields hybrid membranes that combine the antigen-presenting prowess of mature DCs with the homing precision of tumor cells. This hybridization leverages the tumor membrane's homologous targeting traits to bolster the precise delivery of therapeutics, synergizing chemotherapy and immunotherapy [51]. Additionally, tumor cells' propensity for antigenic variation [170] resulting in certain epitope-specific immune deficiencies, renders DCs membranes carrying limited tumor antigens inadequate. Hence, activating a broad spectrum of antigens circumvents immune evasion due to tumor heterogeneity and genetic alterations. The fusion membrane, integrating the qualities of both progenitor cell types, provides a continuous array of tumor antigens. During co-culture, dendritic cells internalize and process an extensive repertoire of tumor-associated antigens (TAAs), which are then displayed on the membrane surface via the major histocompatibility complex, fostering DCs maturation and upregulation of costimulatory molecules CD80 and CD86. This process ensures the presentation of a comprehensive antigen set to lymphocytes during immune activation [171, 172]. By leveraging only the plasma membrane of hybrid cells, this approach sidesteps issues such as oncogenic risk and low viability associated with genetic material [166].

Currently, two predominant strategies have been employed for the generation of hybrid membranes. The initial and more straightforward approach involves individually preparing dendritic and tumor cell membranes and subsequently amalgamating them via sonication fusion techniques [51, 173]. Alternatively, bone marrow-derived dendritic cells and neoplastic cells are coalesced [28, 165, 166, 172] within a specialized medium (e.g., polyethylene glycol), followed by hypotonic lysis, serial freeze–thaw cycles, and sonication to directly yield a composite membrane [28, 174]. This fusion procedure prompts the maturation of dendritic cells and the enhancement of costimulatory molecules' expression. Empirical evidence indicates the efficacy of this membrane fusion, with ultrasonic application mitigating protein degradation. Critical ligands such as MHC I and CD80 on DCs membranes, as well as CD44 and ICAM on cancer cell membranes—key to tumoral adherence and invasiveness—are effectively conserved.

Preparation of nanoparticles

Confronting the adverse effects like nephrotoxicity, neurotoxicity, and gastrointestinal damage inherent to conventional drug delivery methods, nanoparticle-based delivery systems are advancing swiftly, garnering increasing focus in the realm of pharmacological conveyance [175]. Optimally dimensioned and shaped nanoparticles facilitate precise targeting and accumulation at disease sites. Moreover, nanoparticles can securely encapsulate, transport, and administer therapeutic agents, comprising immunoadjuvants and chemotherapeutics, where the former augment DCm-induced immunogenic activation and the latter directly ablate proliferative cancer cells.

A biocompatible and non-toxic vector for drug delivery can harbor agents such as IL-2 [159], photothermal compounds, and OXA prodrugs enhancing immunogenicity [168], hotosensitizer [176], rapamycin [163], CpG ODN and so on. Among the plethora of nanoparticles, poly (lactic-co-glycolic) acid (PLGA) NPs [28, 167] stand out, owing to their superior biodegradability, biocompatibility, tunable degradation kinetics, and mechanical properties conducive to processing. Notably, adjusting the monomeric ratio allows for tailored drug release rates [177–179]. Additionally, drug nanoencapsulation mediated by Distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy[polyethylene glycol]-2000) (DSPE-PEG) [51, 163, 164, 168] or Poly (disulfide ester amide) (PDEA) polymers mediated drug nanocrystallization can also stabilize the encapsulated drug and significantly improve hemodynamics [168].

Nanoparticle drug loading can be executed through various methodologies. Commonly, drugs are incorporated via the nanoprecipitation technique [51, 163, 164, 168]. For insoluble chemotherapeutic agents, nanosuspensions enhance the drug load and bioavailability, amplifying drug concentration at the intended site. The versatility of nanoparticles in terms of surface modification for targeted delivery also enables their integration with aDCm or hybrid membrane coating technologies to broaden the spectrum of novel formulations [180]. Employing ultrasonic precipitation and double emulsion methods [28, 32, 174], insoluble drugs dissolved in an oil phase are emulsified into an aqueous phase under ice-cooled ultrasonic conditions, followed by agitation to produce stable nanoparticles [51].

Fusion of DC membrane and core nanoparticles

Dendritic cell-derived membranes retain antigen-presenting capabilities independent of the source cell's structure, size, and viability. Nanoparticles carrying and dispensing drugs ensure a degree of drug concentration at the tumor locus. Nonetheless, due to the inherent low targeting and biocompatibility of nanoparticles and their rapid immune clearance, coating them with biomembranes derived from dendritic cells is crucial. Post a series of processes including hypotonic lysis and sonication, an advanced dendritic cell membrane (aDCm) is procured. The aDCm can be coated onto PLGA-NPs through ice bath sonication, or reconstituted into microcapsules via pressure-induced rupture utilizing a multifaceted microfluidic platform [160, 164, 174]. Such sonication and encapsulation processes are instrumental in minimizing protein loss (Fig. 4).

Fig. 4.

Schematic illustration for preparation of dendritic cell membrane-coated drug-loaded nanoparticles. The schematic diagram shows that mature dendritic cells are stimulated by a tumor cell lysate, and the plasma membrane is re-suspended by different operations. The NPs coated with the DC membrane activated by the corresponding cancer cell membrane or the membrane hybridized with the DC were injected into the tail vein of the model mice to verify the immunotherapy and immune prevention of the delivery vector for the mice

Characterization/properties mediated by biomimetic nanoplatform

3.5.1 Physicochemical properties

The biomimetic nanoplatform exhibits a consistent core–shell morphology with a diameter exceeding 100 nm [28, 32, 51, 163, 176]. Particle size has a complex effect on the transport and retention of lymph nodes, and is affected by the injection route [181]. Simultaneously, the nanoparticles around 50–100 nm are beneficial to the accumulation of lymph nodes due to their nano-size effect, drainage kinetics, lymph node penetration and distribution, and facilitate antigen retention and lymph node presentation at dendritic cells [182, 183]. Sonication enhances the reduction in particle size, promoting stability through minimized nucleation [51]. The hydrodynamic radius of these nanoparticles is augmented by approximately 10–20 nm when compared to uncoated nanoparticles, mirroring the bilayer cellular membrane thickness [32, 51, 173]. This increment substantiates the single-layer plasma membrane encapsulation from dendritic cells [164]. A notable increment in nanoparticle stability and controlled release is achieved through the application of an aDCm coating. Empirical studies confirm the biomimetic nanoparticles' substantial stability in both PBS Empirical studies confirm the biomimetic nanoparticles' substantial stability in both PBS [163], and plasma environments [163, 176]. The stability of the particle dispersion system is directly proportional to the zeta potential, correlating to the charge reversal of the biomimetic nanoparticles [51, 168] and their optimal nano-dimensions. Experimental evidence suggests that this stability contributes to extended blood circulation times [163, 166], resulting in decreased toxicity and heightened in vivo biosafety [51] and biocompatibility [32]. These nanoparticles maintain stability with minimal drug leakage at ambient temperature.

Under acidic conditions, the membrane-encapsulated biomimetic nanoparticles rapidly discharge their drug payload in PBS, enhancing drug concentrations at the target site [51]. The release rate in acidic conditions surpasses that in neutral or alkaline settings [173]. The TME, characterized by an acidity due to anaerobic glycolysis by tumor cells, prompts a pH-responsive drug release from the nanoparticles. This release profile indicates an improvement in stability and controlled release kinetics. Preservation of protein content is optimized through lyophilization and storage at −20 °C.

3.5.2 Biological properties

Dendritic cells, upon stimulation, exhibit a marked increase in antigen presentation, evidenced by elevated expression of MHC I and II and co-stimulatory molecules (CD80, CD86, etc.) [172]. The consistent expression of MHC-I, MHC-II, and co-stimulatory molecules like CD80, CD86, and ICAM-1 is foundational for dendritic cell-mediated immune presentation, crucial for T cell activation. Research indicates that dendritic cell membrane vesicles can specifically target lymphoid tissues and activate T cells, with derived DCs demonstrating high biocompatibility [184, 185]. Encapsulation by active dendritic cell membranes endows nanoparticles with mature DCs membrane physiological characteristics, facilitating longer bloodstream residence, targeted migration, and biological barrier traversal [176]. The biomimetic nanoparticles preserve biological activity within their shell structure, which is vital for eliciting an immune response. They retain essential membrane markers such as MHC-I, MHC-II, and co-stimulatory molecules (CD86, CD80, CD11c, and CD40), confirming the effective preservation of characteristic proteins post encapsulation [28, 32, 163, 164, 173, 176]. The correct orientation of the coated membrane replicates the source cells, sustaining membrane functionality. The continuous delivery of antigens by the plasma membrane elicits a robust immune response, disrupting the tumor's immunosuppressive microenvironment. Presenting a full repertoire of tumor-associated antigens (TAAs) and co-stimulatory signals maximizes immune activation, circumventing immune escape due to antigenic heterogeneity.

Moreover, the upregulation of the CCR7 lymph node homing receptor enhances guidance to lymphatic structures, while tumor cell surface antigens exhibit homotypic adhesion properties [186–188]. Following dendritic cells' co-culture with tumor-conditioned lymphocytes, tumor antigens are efficiently displayed on the surface of aDCm and are preserved effectively. Consequently, the biomimetic nanoplatform maintains both the antigen-presenting capability of dendritic cells and the homotypic adhesion feature of tumor antigens [163]. Cell internalization is most efficient through membrane-to-membrane recognition [189]. It is postulated that the fusion of DC-derived lipid bilayers with accessible tumor cell membranes enhances the uptake of nanoparticles, thereby increasing their accumulation within tumor sites due to the nanoparticles' increased internalization efficiency [168]. The conjugation of activated DC membranes, the intrinsic targeting property of tumor antigens, and the augmented permeability and retention effect due to the nanoparticle size synergistically establish a theoretical basis for enhanced drug delivery to the target area.

The safety profile of the biomimetic nanosystem is demonstrated by its use as a therapeutic or prophylactic agent, which does not induce significant weight loss or tissue damage in major organs of mice [28]. Additionally, the nanoparticles exhibit increased accumulation and prolonged retention at the lymph nodes and spleen near the injection site [172], confirming the system's targeted delivery and biocompatibility [163]. Cellular-level research, including in vitro hemolysis assays and in vivo assays of serum hepatic enzymes and renal function parameters, further corroborate the biomimetic nanoparticles' biocompatibility, extended metabolic duration, and circulation time [168, 190]. Drug targeting improvements and pH-responsive release significantly mitigate potential drug side effects [168, 191].

4. Application of DC membrane-encapsulated biomimetic nanoparticles inducing immune response and combination therapy

Contrasting with other antigen-presenting cells such as macrophages, dendritic cells uniquely activate naive T cells, catalyzing the body's T cell immune response and serving as potent immune adjuvants [192]. DC membranes retain the original cells' characteristics, including the ability to traverse physiological barriers [173]. Nanoparticles coated with DC membranes activated by cancer cell membranes or membranes hybridized with DCs have been validated for immunotherapeutic and immunoprophylactic efficacy in murine models [28, 32]. These hybrid membranes present persistent cancer antigens from cancer cell membranes, eliciting robust immune responses against tumor cells. The aggregation of biomimetic particles in tumor regions is facilitated by the adhesive domains of tumor cytoplasmic membranes and specific binding proteins [166], as well as membrane-surface tumor antigens' targeting capabilities [173].

However, the tumor immunosuppressive microenvironment hinders immune cell accumulation [47]. The TME fosters immune tolerance by inducing the formation of tolerogenic dendritic cells and anergy in CD8⁺T cells. Additionally, diverse immune evasion tactics developed by cancer cell clones render them less susceptible to various therapies [193], thus complicating cancer treatment. For instance, the TME suppresses dendritic cell recruitment, activation, and antigen presentation, induces cytotoxic T lymphocyte (CTL) anergy and apoptosis, and promotes regulatory T cell (Treg) generation, effectively evading the immune response and achieving immune escape [172]. Chemoresistance in cancer cells is facilitated by the hypoxic and lactic acid-rich microenvironment [194], while overexpression of heat shock proteins [195] confers resistance to thermal stress in photothermal therapy [164]. Nevertheless, the disparity between cancerous and normal cells presents specific targets for tumor cell eradication by activating the immune response and remodeling the TME.

A multitude of experiments have substantiated that biomimetic nanoplatforms exhibit an augmented affinity for T-cell surface binding, thereby enhancing T-cell activation. This interaction precipitates a cascade of cytokine secretion, notably IFN-γ and TNF-α, resulting in a synergistic amplification of T-cell activation [32]. Comparative studies indicate that these nanoplatforms elicit a substantial increase in cytokine production relative to alternative methods, and consequentially potentiate cytotoxic T lymphocyte (CTL)-mediated cytotoxicity upon co-culture with target cells [32]. Despite these findings, the absence of controlled trials directly substituting cancer cells limits the precise quantification of activation efficiency [32].

DCs biomimetic membranes retain the antigen-presenting functionality inherent to DCs, facilitating T-cell activation and proliferation via the interplay between membrane ligands (MHC and costimulatory molecules) and T-cell receptors. Moreover, these biomimetic constructs not only trigger T-cell activation within the tumor microenvironment but also migrate to lymph nodes, inciting the activation of naïve T cells, a process guided by the CCR7 receptor on the DC membrane [160, 164, 165, 172]. The anti-tumoral efficacy of these nanosystems is multifaceted: (1) Mature DC membranes induce maturation in their immature counterparts [173], with the hybrid membrane demonstrating superior dendritic cell activation, attributed to the MHC-mediated presentation of tumor antigens [165]. The immunostimulatory effects of the biomimetic membrane result in the proliferation and differentiation of naïve T cells into effector subsets, CD8⁺ and CD4⁺T lymphocytes. CD8⁺CTLs specifically target and induce apoptosis in tumor cells while concurrently inhibiting tumor angiogenesis [196], and CD4⁺T cells elevate MHC expression, augmenting CTL-mediated tumor cell apoptosis [109, 164, 166]. CD4⁺T cells additionally stimulate CTL proliferation and enhance their tumoricidal activity [51]. Tumor antigens presented on biomimetic nanoparticles incite macrophage activation and subsequent cytokine release, including IL-6, TNF-α, and IFN-γ [51]. (2) T lymphocytes secrete cytokines such as IL-12, IL-2, TNF-α, and IFN-γ, fostering a positive feedback loop that intensifies primary lymphocyte activation. Elevated IL-12 and IFN-γ levels perpetuate the disruption of immune tolerance [164], amplifying the expression of pro-apoptotic regulators and diminishing anti-apoptotic mediators, thereby promoting tumor cell apoptosis [51, 164, 166]. Furthermore, inflammatory cytokines directly induce tumor cell apoptosis through lysosomal destabilization and enzyme leakage, and IL-6 modifies glioma cell glucose metabolism, leading to decreased intracellular pH and oncocyte death [51]. (3) Nanoparticle-conjugated drugs specifically target cells include neoplastic cells and T lymphocytes. For instance, photosensitizers utilized in photodynamic therapy accumulate selectively in tumor cells, initiating photochemical reactions that convert oxygen into cytotoxic reactive oxygen species (ROS). Chemotherapeutic agents carried by nanoparticles enhance cancer immunotherapy by inducing immunogenic cell death (ICD) [176]. The resultant accumulation of dead tumor and immune cells in the target area precipitates immunogenic cell death, propelling the immune cycle towards a favorable outcome [164]. Biomimetic nanoparticles promote the continuous proliferation of T cells by releasing their encapsulated IL-2. Overall, this may be attributed to the nanoscale size effect of biomimetic nanoparticles, which, in comparison to DCs, induces an enhanced T cell activation effect [32, 197].Correspondingly, a shift in the immune cell population is observed, with a decrease in CD3⁺CD4⁺T cells and an increase in CD3⁺CD8⁺T cells, indicative of an alleviated tumor immunosuppressive microenvironment [167]. The ultimate goal of cancer immunotherapy is the precise identification and eradication of cancer cells, culminating in delayed tumor progression and reduced metastasis [32] (Table 2) (Fig. 5).

Table 2.

Dendritic cell membrane coated drug-loaded nanoparticles targeted cancer therapy

Type of membrane	Core nanoparticles	Cargo	Combined treatment	Types of cancer	in vitro model	Mechanisms and functions	Ref.
DCm	PLGA	IL-2	immunotherapy	Ovarian cancer	ID8	1. The activation of T cells is triggered by antigen presentation 2. The nano-size effect helps break through the time and space limitations in the antigen presentation process 3. The inhibition effect of tumor growth delay and metastasis was significantly improved	[32]
DCm	Poly (disulfide ester amide) (PDEA) polymers	Hydrophobic oxaliplatin (OXA) prodrugs	Chemotherapy	Colon cancer	CT26	1. The T cell response is initiated through antigen presentation 2. Immature dendritic cells are activated 3. NPs induce immunogenic cell death, and the mitochondrial pathway induces tumor cell death, thereby creating an immunogenic microenvironment 4. The effector factors of the immune system effectively inhibit the growth and metastasis of distal tumors	[[168]]
DCm	\	Photosensitizers (AIE)	Photodynamic therapy	Breast cancer	4T1	1. T cell proliferation is activated by antigen presentation 2. The AIE photosensitizer can effectively accumulate around the tumor through crossing the biological barrier and hitchhiking	[[176]]
DCm	Poly (lactic-co-glycolic acid) (PLGA)	Rapamycin (RAPA)	Chemotherapy	Glioma	C6, 4T1	1. T cells are recognized and activated directly or indirectly 2. Homotypic targeting is enhanced through the blood–brain barrier 3. Long-term immunotherapy is provided 4. The secretion of immunostimulatory cytokines relieves the immunosuppressive tumor microenvironment	[[163]]
DCm	Distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy [polyethylene glycol]-2000) (DSPE-PEG)	Photothermal agents (IR-797)	Photothermal therapy	Breast cancer	4T1	1. T cells are activated in situ or in lymph nodes to secrete cytokines 2. The expression of heat shock protein in tumor cells is decreased, while heat stress is increased 3. Laser irradiation is used for photothermal therapy 4. Immunogenic cell death is induced	[[164]]
DCm	Cancer cell membrane-coated PLGA nanoparticles	Anti-programmed death-1 antibodies	Immunotherapy	Melanoma	B16-OVA	1. T cells are directly cross-initiated to stimulate a strong, antigen-specific anti-tumor response 2. Cooperation is established with the clinical anti-programmed death-1 antibody	[[167]]
DCm	Histidine-modified stearic acid-grafted chitosan (HCtSA), and DCm/HCtSA/ ovalbumin (OVA) micelles	\	\	Melanoma	B16-OVA	1. Targeting lymph nodes induces cellular immunity 2. Antigen release behaves in a pH-dependent manner	[[173]]
Hybrid membrane based on C6 cell membranes and DC membranes	Surfactant SDC	Docetaxel (DTX)	Chemotherapy	Glioma	C6	1. Drugs are delivered through homologous targeted precise delivery 2. Antigen presentation and immune activation of the downstream immune system occur	[[51]]
Hybrid membrane based on 4T1 cells membranes and DC membranes	Porphyrin-based Zr-MOF (PCN-224)	Nanophotosensitizers	Photodynamic therapy	Breast cancer	4T1	1. Tumors exhibit self-targeting characteristics 2. A photosensitizer is coated for synergistic photodynamic therapy (PDT) 3. The PDT of the primary tumor enhances the regression of a non-radiation distant tumor, caused by immunotherapy	[[166]]
Hybrid membrane based on murine colon adenocarcinoma MC38 cells membranes and DC membranes	PLGA	CpG ODN	Immunotherapy	Colon cancer, brain cancer	MC38	1. T cells are activated upon penetration of immune organs 2. An immune adjuvant is co-delivered	[[28]]
Hybrid membrane based on OC cells membranes and DC membranes	Poly (lactic-co-glycolic acid) (PLGA)	Immune adjuvant CpG-oligodeoxynucleotide (CpG-ODN)	Immunotherapy	Ovarian cancer	ID8	1. T cells are activated both directly and indirectly 2. An immune adjuvant acts synergistically	[[172]]
Hybrid membrane based on 4T1 cells membranes and DC membranes	Silica nanoparticle	R837 Immune adjuvant	Immune checkpoint blockade	Breast cancer	4T1	1. Tumor growth is inhibited by combined immune checkpoint blockade 2. The immunosuppressive microenvironment and immune memory effect are regulated 3. Antigen delivery and homogeneous targeting are achieved	[[225]]
Hybrid membrane based on 4T1 cells membranes and DC membranes	Tetrakis (4- carboxyphenyl) porphyrin (TCPP)	\	\	Breast cancer	4T1	1. Lymph node homing is facilitated 2. T cells are activated by antigens	[[165]]

Fig. 5.

Schematic illustration biomimetic nanoparticles play a role in antigen presentation, and immunotherapy combined with other treatments kills tumors together. The mature dendritic cell membrane retains the ability of antigen presentation, interacts with immune cells, and combines photodynamic therapy, photothermal therapy, cytokine immune killing, and chemotherapy to break the tumor immunosuppressive microenvironment. Biomimetic nanoparticles activate t-lymphocyte through direct and indirect pathways. Among them, the indirect pathway is that immature dendritic cells engulf mature membrane. The direct pathway is that aDCm recognizes and activates naive T cells through TCR. At the same time, DC cells present antigens as antigen-presenting cells and secrete cytokines. By detecting the levels of cytokine TNF-α and IL-6, it is shown that iDC is successfully activated into aDC. DC cells activate T cells to release cytokine of IL-2, IFN-γ, TNF-α, and IL-6, and then natural killer cells proliferate under the action of IL-2 to produce cytokines IFN-γ. During the maturation of DC cells, DC cells capture and process tumor antigens, promote microphages release of cytokines such as IL-6, TNF-α and IFN-γ. TNF-α and IFN-γ can be ingested into the lysosome of cancer cells to cause cancer cell autolysis

Breast cancer

Breast carcinoma is the predominant cancer affecting females and ranks among the top three cancers diagnosed globally [198, 199]. Current therapeutic approaches, integrating surgery with radiotherapy and chemotherapy, have notably diminished breast cancer mortality rates. However, systemic treatments still pose a residual risk for non-breast cancer-related mortality [198, 200]. In research, the utilization of DCs biomimetic membranes in conjunction with modalities like photothermal therapy (PTT) or photodynamic therapy (PDT) has yielded promising outcomes in breast carcinoma management. Conventional photosensitizers suffer from high hydrophobicity, which predisposes them to aggregation and subsequent quenching effects, leading to non-specific targeting of both tumor and immune cells within the tumor microenvironment. Lipid droplet accumulation in breast cancer cells, as evidenced by numerous studies [201], creates a distinct biological marker that differentiates malignant cells from normal somatic cells, thus serving as a potential treatment target. Enhancing the delivery of photosensitizers to primary breast tumors and boosting their tumor-specific cytotoxicity are crucial for advancing breast cancer therapy. PTT and PDT leverage the preferential accumulation of photosensitizers/photothermal agents in diseased tissues, which enables selective cellular destruction upon exposure to appropriate light wavelengths. Given the increased lipid droplet synthesis in breast cancer cells compared to normal cells, this disparity is exploited to target tumors specifically by designing lipid droplet-oriented photosensitizers that augment photosensitizer concentration at the primary tumor site. PDT, as a non-invasive therapeutic modality, garners attention for its distinctive mechanism and precise spatiotemporal control [202]. The nanoplatform's efficacy in triggering a T-cell-mediated immune response is substantiated by the significant elevation of CD8⁺ and CD4⁺T-cell populations in both primary and distal breast tumors [164, 176].

The aDCm-encapsulated biomimetic system targets lipid droplets with donor–acceptor photosensitizers. These biomimetic nanoparticles exploit natural dendritic cell membrane ligands for T-cell binding and are transported to the tumor microenvironment, overcoming biological barriers such as the vasculature. Nanoparticle-encased photothermal agents exhibit superior photothermal conversion efficiency compared to their unencapsulated counterparts due to a collective quenching effect. Photothermal therapy is deemed negligible in heating effect, with less than a 5-degree Celsius temperature increase under 30 min of laser irradiation. Post-PDT, there is significant ablation of the primary tumor and suppression of distant tumor progression [176]. Under mild therapeutic conditions following laser exposure, tumor cells are selectively eradicated while immune cells are preserved [176].

Cytokines within this context play dual roles [164]. They act as regulators by downregulating heat shock protein (HSP) expression in cancer cells treated with the biomimetic nanoparticle system, sensitizing them to heat stress and enhancing PTT efficacy. Concurrently, cytokines serve an immunomodulatory function by diminishing the expression of anti-apoptotic regulatory proteins and upregulating pro-apoptotic ones, thus promoting tumor cell apoptosis and demonstrating the potential of aDCm-coated nanoparticles to induce PTT and immunotherapy synergistically.

The application of biomimetic nanosystems in conjunction with PTT/PDT and as monotherapy significantly restricts the growth of primary and metastatic breast tumors [176]. Nonetheless, the combination therapy exhibits a more pronounced effect, suggesting that nanoparticles can initiate the cancer-immunity cycle for comprehensive immunotherapy. Mice treated with these nanoparticle platforms experience extended survival rates without apparent adverse effects [164, 176]. Furthermore, biomimetic nanoparticles sustain immunotherapy effects and curb primary tumor recurrence post-therapy.

In vivo studies, our biomimetic nanoparticles can effectively induce systemic and tumor-specific immune responses in model animals with breast cancer. Specifically, the percentage of T cells in draining lymph nodes was significantly higher. In addition, flow cytometry analysis of the spleen showed that CD8⁺IFNγ⁺ effector T cells were significantly increased in immunized animals. The levels of IFNγ and TNFα in serum were also two to three times higher than those in the control group. After prophylactic inoculation of DC biomimetic membrane nanoparticles, the tumor volume was significantly smaller and the survival time was significantly longer than that of all other groups at each time point (Fig. 6).

Fig. 6.

The mechanism of action of biomimetic nanoparticles in breast cancer. I.In addition to the ability of lymphatic homing, the hybrid cell biomimetic membrane of dendritic cells and cancer cells also shows the ability to directly activate the antigen presentation ability of T cells and induce the maturation of DC, so as to achieve preventive immunotherapy. II.Biomimetic membrane-coated nano-photosensitizers cause a sustained immune response to inhibit the rebound of primary tumors after nano-photosensitizer-induced photodynamic therapy (PDT). PDT of primary tumors enhances the regression of radiation-free distant tumors caused by immunotherapy. III.The combination of lipid-targeted photosensitizer AIE and antigen-presenting carrier platform for efficient drug delivery and cancer immunotherapy. IV.The hybrid biomimetic membrane obtained by dendritic cells and tumor cells, using MSN as a nanocarrier and R837 as an immune adjuvant, can effectively stimulate DC maturation and antigen presentation, inhibit tumor growth and regulate tumor immune microenvironment to inhibit tumor recurrence. V.The dendritic cell biomimetic membrane was coated with photosensitizer IR-797 to initiate T cells by in situ cross-priming or drainage to lymph nodes. The expression of heat shock protein in tumor cells decreased, and tumor cells were more sensitive to heat stress. After mild photothermal therapy-laser radiation and photosensitizer induced tumor cell death, dead tumor cells and surviving immune cells initiated the self-sustaining cycle of cancer immunity

Ovarian cancer

Ovarian cancer (OC) constitutes a major public health issue, ranking as the fifth most prevalent cause of cancer-related mortality among women and the most lethal gynecological malignancy [203]. Globally, OC is the third most common gynecological cancer and the second leading cause of death from such cancers. Primary surgical intervention followed by adjuvant chemotherapy represents the standard of care for OC. Most cases of OC disseminate early, necessitating systemic chemotherapy with platinum-based agents and paclitaxel as a critical component of subsequent management [204]. Although systemic chemotherapy can be profoundly detrimental to patient well-being, immunotherapy has emerged as a critical therapeutic modality for OC. However, immunotherapy for OC is currently supported only by limited preliminary studies, and its clinical application remains to be instituted.

Advancements in DC-mimicking biointerfaces have shown promise in OC therapy. Researchers have engineered biomimetic nanoparticles by enwrapping IL-2-loaded poly (lactic-co-glycolic acid) nanoparticles (PLGA-NPs) with membranes sourced from mature DCs pulsed with tumor cell lysates [32]. These nanoparticles preserve DC membrane functional proteins, enabling antigen presentation and sustained IL-2 release to stimulate lymphocyte-mediated anti-tumor immunity. Notably, IL-2 is the first cytokine to receive approval from the US Food and Drug Administration (FDA) for cancer treatment [205]. Nanoparticles activate T lymphocytes with thrice the efficiency and cytokine secretion rates of bone marrow-derived DCs. Furthermore, at low effector-to-target ratios, DCs stimulated by biomimetic nanoparticles demonstrate enhanced cytotoxicity [32]. These nanoparticles promote significant secretion of proinflammatory cytokines such as IFN-γ, TNF-α, and IL-6 from T cells, indicative of activated cytotoxic T cell responses. Cytokine uptake by target cell lysosomes impairs lysosomal stability, resulting in enzyme release and tumor cell lysis. Additionally, IL-6 alters glucose metabolism in tumor cells, decreases intracellular pH, and induces cancer cell death [51]. OC commonly metastasizes to the abdominal and pelvic cavities OC commonly metastasizes to the abdominal and pelvic cavities [206], but in vitro studies have shown that biomimetic nanoparticles appreciably reduce metastatic tumor nodule count and size on the abdominal wall. In vivo results include thymus enlargement and heightened CTL infiltration in ovarian tumors, leading to extensive tumor cell apoptosis, a prognostic indicator for OC patient survival [207]. The proportion of immune cells such as NK cells in the tumor microenvironment increases, and the immune microenvironment improves and reshapes, providing continuous prevention and protection for the body after treatment, and inhibiting tumor metastasis or recurrence [163]. In terms of safety, hemolysis test verified its good biocompatibility in vitro. The biomimetic nanoplatform outperforms traditional DCs in hindering the progression of advanced OC, fostering systemic and tumor-specific immune responses in murine models. (Fig. 7).

Fig. 7.

The mechanism of biomimetic nanoparticles in ovarian cancer and glioma. Mature dendritic cell membrane-loaded cytokines or chemotherapeutic drugs play an enhanced T cell response in vitro and in vivo. In ovarian cancer, tumor growth is delayed and metastasis is inhibited in vivo. In glioma, the isotype targeting mechanism of glioma and the penetration of blood–brain barrier are beneficial to chemotherapy and immunotherapy in the brain

Neuroglioma

Glioma, a highly fatal malignancy, represents the predominant type of primary intracranial tumor, accounting for 80% of all malignant central nervous system neoplasms [208]. The immunosuppressive tumor microenvironment and the blood–brain barrier (BBB) are significant challenges in brain tumor therapy. Overcoming these barriers is a potential strategy for enhancing immunotherapy efficacy. Both physiological (BBB) and pathological (blood–brain tumor barrier) barriers impede drug access to the brain [209]. Brain tissue is notably more susceptible to cytotoxic drug damage than other organs, hence, strategies that enable effective transit or circumvention of the BBB and selective targeting of tumor cells are critical to mitigate drug-induced cerebral damage [209]. Historically, glioma treatments have centered on inhibitor design [210, 211], but the extensive immunosuppression by gliomas results in rapid single-agent antibody clearance [212]. Contemporary immunotherapy strategies aim to bolster T cell responses, exemplified by the administration of vaccines and drug delivery via DCs membrane-coated nanoparticles.

The protein known as Glial Fibrillary Acidic Protein (GFAP), recognized as a marker for gliomas with enhanced differentiation and reduced malignancy [213, 214], exhibits notable suppression of glioma proliferation and possesses a high capability to trigger differentiation in these tumors [163]. Furthermore, the C6 membrane exhibits tumor-targeting properties, selectively binding to and identifying C6 cells. This specificity facilitates the delivery of nanoparticles across the blood–brain barrier and into the tumor matrix, thereby augmenting the local concentration of therapeutic agents at the glioma site and reducing systemic toxicity and adverse effects, markedly extending the lifespan of glioma-bearing mice [51]. The retention of CD44 and ICAM, molecules critical for targeted adhesion and invasion, has been verified within the C6 membrane, enhancing the blood–brain barrier penetration of nanoparticles, improving infiltration into brain tumors, and increasing the efficiency of drug uptake by glioma cells. Nanoparticles derived from dendritic cell membranes, activated by tumor antigen lysates, offer a continuous source of tumor antigens that activate and mature DCs, while also stimulating macrophages and other immune cells to secrete cytokines. Consequently, these biomimetic nanoparticles harbor substantial research potential.

Biomimetic nanoparticles demonstrate increased accumulation within the spleen and lymph nodes, notably elevating CD4⁺ and CD8⁺T-cell populations within the spleen. The immunogenic vaccine formulation significantly boosts CD8 proliferation at every measured time point and raises peripheral blood CD8 counts, surpassing the pure nanoparticle (NP) drug formulations lacking immunogenic properties in the control group [28], co-localization cells [215] and inhibiting tumor cell proliferation [215]. The proportion of CD80⁺ and CD86⁺ DCs and the percentage of CD4⁺ helper T cells were significantly increased. The expression of CD8 and CD4 in the tumor site was significantly increased after treatment with biomimetic nanoparticles by IHC and immunofluorescence staining. ELISA showed that cytokines such as TNF-α, IFN-γ and IL-6 in serum were also significantly increased at the glioma site after biomimetic nanoparticles, which could inhibit the rapid growth of glioma more quickly. The improvement of drug loading capacity significantly increases the drug concentration at the target site, which can penetrate deeper glioma tissues. After treatment, the median survival time was significantly increased, the tumor cell density was significantly decreased, and it had a good potential to induce glial cell differentiation [32]. Additionally, the technology integrates hybrid membrane systems with nanosuspension functionalization to create a targeted delivery system for the chemotherapeutic agent docetaxel (DTX), encapsulated within hybrid membrane-coated drug-loaded nanoparticles [51]. In vitro studies demonstrate a specific drug release pattern for the biomimetic system; in a simulated tumor acidic environment, the encapsulated drug is rapidly released, achieving concentrations suitable for chemotherapy, providing a foundation for effective drug release at the target site. (Fig. 7).

Melanoma

Melanoma is the most aggressive form of skin cancer, characterized by life-threatening and rapidly spreading progression [216]. TAt present, there is no difference in progression-free survival and overall survival between multiple chemotherapy and single chemotherapy. Compared with chemotherapy, biochemotherapy did not significantly improve overall survival [217]. Traditional targeted therapy can alleviate tumors by inactivating overactive kinases such as BRAF or MEK, but inevitably encounter drug resistance. The emergence of immunotherapy has completely changed the treatment of melanoma and significantly improved the prognosis of melanoma patients. However, immune-related adverse events in immunotherapy can affect one or more organs and may limit their use [218]. Therefore, it is particularly important to find a suitable way to enhance tumor growth inhibition and improve survival rate.

The dendritic cell membrane generated by the cascade coating retains the constituent proteins of the membrane and the intrinsic function of the membrane. Unlike endogenous dendritic cells, T cells are induced by BNs direct cross-primers, bypassing the need for conventional antigen processing and presentation, and can cause a strong antigen-specific T cell response. By blocking the immune checkpoint by preventing PD-1 on T cells from binding to programmed death ligand 1 (PD-L1), CTL can be activated to attack cancer cells. The biomimetic platform was used in combination with clinical αPD-1 and its anti-tumor response was evaluated in a more clinically relevant therapeutic environment. It also inhibits the growth of in situ tumors and prolongs the survival period. In the case of a decrease in CD4⁺ T cells, CD8⁺ T cells and cytokines increase. The biomimetic platform produces strong antigen-specific anti-tumor immunity in an invasive but ova-expressing melanoma model [167].

Compared with peripheral dendritic cells, lymph node dendritic cells show higher antigen transfer effect, because they can be activated by small doses of antigen [219]. Direct vaccination to lymph nodes is considered to be an effective strategy for anti-tumor immune response. The test medium with different pH values was studied to simulate the antigen release behavior of dendritic cells. With the decrease of pH (pH 6.5 and 5.0, respectively), the cumulative release efficiency increased. Studies have shown that when the pH value is 5.0, the cumulative antigen release efficiency of the bionic platform reaches the highest within 24 h. Spleen hypertrophy, lymph node hyperplasia, and the percentage of activated T cells increased. Important biologically active cytokines such as IFN-γ, TNF-α, IL-12 and IL-6 associated with anti-tumor immune response were significantly increased, indicating that the combination therapy induced a strong systemic immune response [167, 173]. The biomimetic nanoplatform significantly improved the expression of CD86 and CD40, showing strong lymph node targeting ability and obvious lymph node retention, thereby enhancing the anti-tumor immune response by long-term stimulation of the immune system, which can further target lymph node dendritic cells to promote antigen uptake, thus arousing great anti-tumor potential [173].

Colon cancer

Colon cancer is one of the most aggressive types of cancer, and colon cancer cases currently rank fourth in the global cancer incidence [220, 221]. The side effects of existing chemotherapy and the possibility of developing resistance to treatment underscore the importance of developing new treatment options. The use of immunotherapy has shown promising results, but the research data for this method is limited [222]. The development of nanotechnology has introduced the application of nanoparticles (NPs) as a promising method for the diagnosis and treatment of colorectal cancer [223]. Therefore, the development of biomimetic membranes has enabled the application of biomimetic membrane-coated nanoparticles in colon cancer.

Prophylactic inoculation of biomimetic nanoparticles promoted the production of IFN-γ and TNF-α in CD8⁺ T cells. It can effectively protect the body from tumor invasion. Even if tumors occur, the infiltration of CD4⁺ and CD8⁺ T cells in the tumor site is significantly greater than that of other NPs, and prophylactic inoculation does not lead to weight loss and histological damage to major organs. Compared with chemotherapy, biomimetic nanoparticle therapy increased the infiltration of CD4⁺ and CD8⁺ T cells in tumors, as well as increased tumor cell apoptosis and growth inhibition. Compared with the NPs of single cancer cell membrane, the accumulation of NPs wrapped in fused cell membrane in spleen and lymph nodes was significantly increased. These NPs are composed of biodegradable polymer PLGA, which allows encapsulation and controlled release of immune adjuvants. Together, they enhance the overall anti-tumor immunity of biomimetic nanoparticles [28, 168].

Prospects and challenges

Advances in cancer immunotherapy have been remarkable, with several modalities gaining clinical approval, such as targeted therapies, immune checkpoint inhibitors, and cellular immunotherapies. A landmark event was the 2011 market introduction of ipilimumab, the first immune checkpoint inhibitor, which blocks T-cell activation pathways by targeting receptors and ligands like CTLA4, PD1, and PDL1 [224]. This marked a significant milestone in the establishment of immunotherapy in oncological treatment. Furthermore, the FDA has sanctioned a multitude of monoclonal antibodies for cancer therapy. Cancer immunotherapy encompasses cytokine therapy, immune checkpoint blockade, adoptive cell therapy (ACT), cancer vaccines, DCs therapy, antibody–drug conjugates (ADCs), among others. Advances also extend to targeted, photothermal, and photodynamic therapies, though side effects remain an inherent challenge. Personalized tumor treatment is nascent, with limitations stemming from a lack of potent antigens, the monoclonal nature of immune response, and the absence of co-stimulatory molecules [28]. Effective cancer eradication and immunization hinge on sustained antitumor responses, a feat difficult to achieve with monotherapies. Overcoming these barriers is possible through the application of biomimetic membranes.

The nanoscale, biomimetic architecture of these particulates preserves the native surface properties and functionalities of their source cells, with the cell-derived membrane exhibiting enhanced in vivo stability. Research predominantly focuses on erythrocyte, neoplastic, and thrombocyte membranes, which, in comparison to antigen-presenting DC membranes, demonstrate a deficiency in targeting capabilities and immune activation potential. Consequently, DC membrane-driven release mechanisms present a more promising area of study. The anti-carcinogenic efficacy of DC membrane-coated nanoparticles is multifaceted, encompassing both drug-mediated cytotoxic effects and the immunogenic potential of the membrane. Preliminary evidence [163] suggests their utility as prophylactic oncology vaccines, hinting at their significant prospective role in tailored immunotherapeutic applications across diverse cancer types. These biomimetic DC membranes can be both sustainably stored and widely distributed [32], effectively circumventing the immunosuppressive challenges within the TME that impede T cell aggregation, DC infiltration, their subsequent activation, and antigen presentation [176].

The autologous aDCm incites a targeted and enduring immune offensive against specific neoplastic antigens, restoring control over tumor proliferation [160]. Recent research marrying precise oncotropic drug conveyance with antigen presentation has shown promise, potentially paving the way for efficacious personalized neoplastic treatments [51]. Biomimetic nanoparticles not only facilitate tumor eradication but also proffer long-term immunological prophylaxis against tumorigenesis. Leveraging nanoscale and biomimetic advantages, these particles surpass conventional therapy modalities in cancer treatment. Their diminutive size augments the temporal and spatial efficacy of antigen presentation, thereby eliciting a more robust T cell response compared to adoptive cell transfer (ACT) [32]. Unlike the co-culture of malignant and dendritic cells for adoptive therapy, biomimetic nanoparticles avoid issues such as low viability and storage challenges. Moreover, the pure membrane hybrids, devoid of genetic material, offer a safer alternative to gene transfection, with enhanced tumor penetration and an ability to navigate the constraints of the TME [28]. Being non-living entities, these nanoparticles have extended shelf lives and resist immunosuppressive conditions, obviating the need for the complex, costly in vitro optimization required by DC adoptive therapies.

These therapeutic nanoparticles serve as a universal scaffold for integrating functional materials with an array of pharmaceuticals, tailored to specific disease states and drug attributes, particularly those with low solubility, high toxicity, and difficulty in traversing physiological barriers. The DC membrane-based nanoplatform for tumor-specific immunotherapy holds potential for expansion across various cancer types, offering versatile nanoparticle configurations for distinct biochemical functions [166]. The amalgamation of homologous cancer cell and DC membranes encapsulates a drug delivery system, facilitating the convergence of immunotherapy with other treatment modalities [51]. With the specific tumor antigen recognition capabilities of dendritic cells and the homologous targeting of cancer cell lines, it is reasonable to anticipate that DC membranes activated by various tumor lysates, or hybrid membranes from the fusion of dendritic cells with different neoplastic lines, can integrate with conventional cancer therapies for enhanced therapeutic outcomes. Autologous DCs and tumor cell lines can be extracted directly from patients, ensuring an antigenic match that elicits a robust immune response, thereby mitigating the issue of suboptimal treatment associated with the heterogeneity of homologous tumors. This approach heralds a shift from traditional, non-discriminatory therapies such as surgery and chemotherapy to more precise, targeted treatments.

Despite these advances, the field lacks rigorous positive control trials that include comparisons to standard clinical treatments, and research has been limited to evaluating the stimulatory effects of dendritic cell membranes on T cells and macrophages in immunotherapy settings, with studies confined to murine models. Future investigations could benefit from employing humanized mice to yield data more representative of human physiology. Current exploration into dendritic cell membrane-coated nanoparticles for cancer immunotherapy is nascent, with a substantial need for expanded experimental and data collection efforts. It is imperative that more researchers engage with the significant potential of this modality.

Summary and appeal

Dendritic cells play a pivotal role in the pathogenesis of numerous diseases, presenting as prospective pharmacological targets in disease progression prevention. Integrative DC membrane-based immunotherapy, when used in conjunction with other modalities like PTT, PDT, and chemotherapy, has shown promise in safety and efficacy in preliminary trials. The innovative, multimodal biomimetic nanotherapy leveraging dendritic cell membrane-coated nanoparticles presents a formidable potential in oncological treatment.

Author contributions

TY, HQ, JZ and YLdesigned the study. HL, YL, XL collated the data, carried out data analyses, and produced the initial draft of the manuscript. HL and YL contributed to drafting the manuscript. HL, YL, XL, TY, HQ, JZ, YL and BZ viewed and approved the manuscript. All authors read the manuscript and approved the final manuscript.

Funding

This work was supported by National Natural Science Foundation of China (No. 82270442, 82370425) and and The Natural science foundation of Shandong Province (grant no. ZR2022MH027).

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate.

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.