Novel perspectives on extracellular vesicles in autoimmune diseases: immunogenicity, inflammation, and immune surveillance

Cells release extracellular vesicles (EVs) with cargo that originates from distinct subcellular compartments, including the nucleus, cytoplasm, and plasma membrane. Given their diverse cargo, EVs play multiple roles in physiology and pathology, including in immune dysregulation and autoimmune pathogenesis. For example, EVs can act as autoantigens by transporting immunogenic molecules from the nucleus or cytoplasm, whereas EVs carrying membrane-bound MHCs from antigen-presenting cells can activate adaptive immunity by presenting self-antigens to T cells. EV-associated cytoplasmic peptidases or proteasomes contribute to immune regulation by modulating antigen processing and presentation. Moreover, EVs also drive inflammatory responses by shuttling a variety of proinflammatory molecules that sustain autoimmune responses. Intriguingly, emerging evidence indicates that EVs might contribute to autoimmune surveillance by activating cytosolic surveillance sensors, modulating immune checkpoints, regulating NK/T cell cytotoxicity, and altering macrophage and DC phagocytosis, representing an exciting and underexplored frontier in autoimmune research. By tackling critical knowledge gaps, this Review explores the emerging roles of EVs and their diverse cargo in driving autoimmune diseases, suggesting new perspectives on their potential as innovative therapeutic targets.

EVs are highly heterogeneous in size, shape, origin, cargo, and biological function (21). Based on size and biogenesis, they are classified into the following categories: microvesicles (MVs; 100–10,00 nm), formed through plasma membrane budding (15); exosomes (30–100 nm), generated within endosomal multivesicular bodies (MVBs) and released via exocytosis (22); and apoptotic bodies (1,000–5,000 nm) (1, 23), released during late apoptosis, containing organelles and fragments of the disintegrated nucleus (1, 15, 24). Notably, membrane vesiculation and blebbing during apoptosis lead to the release of various types of apoptotic cell–derived EVs, including exosome-like vesicles, MVs, apoptotic bodies, fragmented beaded apoptopodia, and the remnant apoptotic cell body (2, 9, 14, 23).

EVs can also be released during other forms of PCD (2, 25). Pyroptotic cells release EVs that carry gasdermin D (GSDMD), caspase-1, Fas-associated death domain (FADD), and cytokines, which results in promotion of inflammatory responses (2, 26). Necroptotic cells release EVs (0.2–0.8 μm) that carry phosphorylated mixed lineage kinase domain-like (MLKL) and endosomal sorting complex required for transport III (ESCRT III) components (27, 28), with exposed phosphatidylserine (PS) that promotes immune recognition (27). Unlike apoptotic bodies, necroptotic EVs contain minimal DNA/RNA (28). NETosis, a unique proinflammatory neutrophil death mechanism characterized by neutrophil extracellular trap (NET) formation (29, 30), also releases EVs (31). Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation (32), releases ferroptosis-dependent EVs that can transport iron-loaded ferritin to recipient cells, promoting DNA damage and carcinogenesis (25).

As a fundamental biological process, cell death can be immunologic or nonimmunologic, depending on the specific cellular mechanisms, the cellular components released, and the surrounding microenvironment (33, 34). Under pathological conditions, multiple types of PCD — including apoptosis, pyroptosis, necroptosis, NETosis, and ferroptosis — serve as potent sources of damage-associated molecular patterns (DAMPs) (1, 2, 14). These PCD pathways often converge into an immunogenic cell death phenotype, which is characterized by the release of DAMPs and the exposure of cryptic nuclear and cytoplasmic autoantigens (33, 34) following the nuclear and plasma membrane breakdown and subcellular compartment disruption. Furthermore, the dynamic membrane budding and remodeling during PCD drives EV formation (35, 36), enabling the selective packaging of immunogenic molecules into EVs. Consequently, PCD-derived EVs can transport various immunogenic cargo, thereby contributing to autoimmune pathogenesis (37) and immune surveillance (38, 39).

During EV biogenesis, molecular components from the nucleus, cytoplasm, and plasma membrane can be selectively incorporated into EVs. The nuclear envelope, composed of lipid bilayers and a meshwork of lamin protein, may rupture under certain conditions, leading to the release of immunogenic and proinflammatory nuclear contents (30, 31, 40). Nuclear envelope budding exports nuclear molecules (41, 42) to the cytoplasm and plasma membrane, enabling their release via EVs (14, 43, 44). In activated macrophages, high-mobility-group box 1 (HMGB1) can exit the nucleus through chromosome region maintenance-1–mediated (CRM1-mediated) export, incorporate into the plasma membrane, and then be released via EVs (14). Damaged nuclear DNA can form cytoplasmic micronuclei (45), which may be packaged into EVs (43, 44) and trigger type-1 IFN (IFN-I) production in innate immune cells (31, 40). Moreover, EVs can encapsulate cytoplasmic molecules and organelles, including mitochondria, the Golgi apparatus, endoplasmic reticulum, and lysosomes (46, 47). During EV biogenesis, the cytoplasm acts as a reservoir for nuclear autoantigens (48), DAMPs (14), and micronuclei (45), which are subsequently packaged and released within EVs. Furthermore, plasma membrane proteins (receptors, integrins, ion channels, and enzymes) (14, 49) can be released through membrane vesiculation during MV formation (2, 14). Additionally, extracellular molecules like complement proteins (50) and lipoproteins (51) can be incorporated into EVs, forming a protein corona (51).

The mechanisms governing the export of nuclear/cytoplasmic contents, incorporation of plasma membrane/extracellular molecules, and selective cargo packaging into EVs remain largely unclear. However, recent studies indicate that EVs package subcellular cargo selectively, rather than randomly, through several interconnected mechanisms (21, 52). (a) The ESCRT machinery (ESCRT-0/-I/-II/-III) is essential for sorting cargo into MVBs, which are then released as EVs (52). (b) Lipid rafts are cholesterol/sphingolipid-rich microdomains that contain glycosylphos-phatidylinositol-anchored proteins, signaling molecules, and MHC (53). Lipid raft–associated ceramides induce membrane curvature and budding, while lysophospholipids facilitate selective incorporation of raft-associated molecules into EVs during vesiculation (54). (c) Tetraspanins, a conserved group of transmembrane proteins, form tetraspanin-enriched microdomains by interacting with proteins, glycoproteins, and lipids (55), facilitating EV cargo sorting by clustering molecules and recruiting EV biogenesis machinery (56). Depletion of specific tetraspanins impairs EV release (54). (d) RNA-binding proteins (RBPs) like the heterogeneous nuclear ribonucleoprotein (hnRNP) family, Y-box binding protein 1 (YBX1), and annexin A2 (ANXA2) are crucial for the selective packaging of both coding and noncoding RNAs into EVs (52). Multiple RBPs can synergistically facilitate RNA sorting (57). (e) Posttranslational modifications (PTMs), like ubiquitylation, glycosylation, and phosphorylation, can influence selective protein sorting into EVs (52, 58), though their roles in EV biogenesis require further investigation (58). The sorting mechanisms for mitochondrial DNA (mtDNA) (52) and nuclear molecules into EVs or apoptotic bodies, respectively, remain incompletely elucidated. In late-stage apoptosis, diminishing cellular regulation may result in the incorporation of nuclear molecules into apoptotic bodies via both active and passive mechanisms, though their relative contributions remain unclear.

Growing evidence demonstrates that EVs contribute to autoimmune pathogenesis by transporting immunogenic cargo from nuclear, cytoplasmic, and plasma membrane components (Figures 1, 2, and 3). Dying cells release EVs enriched with danger signals, immunogenic molecules, and immunostimulatory factors (33, 34), which can disrupt immune tolerance, trigger aberrant immune responses, and accelerate autoimmune pathogenesis. EVs may promote autoimmunity through multiple mechanisms, including transport of immunogenic autoantigens (59–61), antigen processing (39) and presentation (62, 63), and modulation of Tregs/Th17 balance (64, 65). Here, we review the current understanding of how EV-associated cargo from distinct subcellular origins contributes to autoimmune pathogenesis via interconnected mechanisms.

Figure 1

EVs with nuclear cargo molecules in autoimmune diseases. (A) EVs package nuclear-derived molecules, including Ro/SSA, La/SSB, Sm RNPs, DEK, DNA, RNA, and lamin B, which serve as immunogenic autoantigens. These molecules promote B cell activation, differentiation, and autoantibody production, while also activating T cells through antigen presentation. EV-associated nuclear autoantigens can further induce immune complex formation, contributing to autoimmune pathogenesis. (B) EVs can also transport nuclear DAMPs, such as HMGB1, S100A9, and histones, which activate immune cells via pattern recognition receptors (PRRs). (C) Notably, infected cells can release EVs containing microbial nucleic acids that stimulate immune cells to produce proinflammatory cytokines through various signaling pathways, including STING. SSA, Sjögren’s syndrome A; SSB, Sjögren’s syndrome B; RNP, ribonucleoprotein; DAMPs, damage-associated molecular patterns; HMGB1, high mobility group box 1; STING, stimulator of interferon genes.

Figure 2

EVs with cytoplasmic cargo molecules in autoimmune diseases. EV-associated cytosolic autoantigens, including vimentin, fibrinogen, citrullinated proteins, G3BP, PR3, and MPO, can promote B lymphocyte activation, autoantibody production, and immune complex formation through binding with autoantibodies, thereby contributing to autoimmune pathogenesis. EVs harboring cytosolic DAMPs, such as mtDNA and HSPs, can stimulate inflammatory cytokine release from innate immune cells and trigger intrinsic immune surveillance. Furthermore, EV-associated cytosolic molecules, including proteasomes, TOP, and DPP-IV, can modulate antigen processing and presentation. EV-associated inflammatory cytokines and inflammasome can activate inflammatory signaling pathways. EVs containing STING oligomers/agonists and perforin are involved in autoimmune surveillance. EV-associated MAVS can promote DC production of IFN-I. In addition, EVs can transport miRNAs involved in immunomodulation. G3BP, galectin-3–binding protein; PR3, proteinase 3; MPO, myeloperoxidase; DAMPs, damage-associated molecular patterns; mtDNA, mitochondrial DNA; TOP, thimet oligopeptidase; DPP-IV, dipeptidyl peptidase IV; STING, stimulator of interferon genes; MAVS, mitochondrial antiviral signaling protein; Mt-molecules, mitochondrial molecules.

Figure 3

EVs with cell membrane and extracellular cargo molecules in autoimmune diseases. EVs can participate in antigen presentation by harboring MHC-I, MHC-II, costimulatory molecules, TCR/CD3 complex, and peptide-MHC complexes, which can activate immune responses and potentially contribute to autoimmune diseases. By carrying diverse membrane molecules, EVs can regulate the activation, proliferation, differentiation, and other functions of various immune cells, including macrophages, DCs, CD8⁺ T cells, Tregs, and B cells. EVs containing NKG2D ligands can inhibit the cytotoxic activity of NK and T cells. EVs containing PD-L1, CD47, CD73, PS, NKG2D ligands, complement, and complement regulators are involved in the process of immune surveillance. Finally, EV-associated protein coronas, complement components, activators/regulators, immunoglobulins, CD40L, and membrane lipids as well as PS may exert pro- or antiinflammatory effects depending on their cargo molecules. TCR, T cell receptor; NKG2D, NK group 2D; PD-L1, programmed cell death ligand 1; PS, phosphatidylserine.

Nuclear molecules are normally hidden from the immune system, so when they are released with EVs they may be misinterpreted as foreign and trigger autoimmune responses. EVs can transport nuclear autoantigens to lymphatic organs, where antigen-presenting cells (APCs) process and present them, activating adaptive immunity (66). EV-associated nuclear DNA may function as a self-antigen to activate autoreactive B cells (59) and stimulate plasmacytoid DCs (pDCs) to produce IFN-I (67). Furthermore, both DNA and IFN-I promote extrafollicular B cell activation (68) and autoantibody production, establishing a self-perpetuating cycle that sustains autoimmunity (68). Supporting this model, in Dnase1l3-deficient mice, impaired DNA degradation in apoptotic MVs triggers anti-DNA antibody production, accelerating lupus pathogenesis (60). Clinically, patients with DNASE1L3 deficiency develop monogenic systemic lupus erythematosus (SLE) characterized by elevated levels of MV-associated DNA (69). Notably, over 50% of patients with sporadic SLE and lupus nephritis exhibit reduced DNASE1L3 activity attributable to neutralizing autoantibodies, further implicating impaired MV-DNA clearance in autoimmune pathogenesis (69). Furthermore, patients with SLE exhibit elevated levels of IgG-, IgM-, and C1q-bearing EVs. Importantly, IgG⁺ EVs correlate with anti-dsDNA antibodies and complement activation (70), two well-established biomarkers of active lupus.

Other nuclear autoantigens, including ribonucleoproteins (Ro/SSA, La/SSB, and Sm/RNPs) (61, 71), RNA (71), HMGB1 (14), histone H3, lamin B1 (72), and DEK (73), can be incorporated into EVs or apoptotic bodies (Figure 1 and Table 1), with significant clinical implications. In patients with SLE, circulating HMGB1-containing nucleosomes contribute to autoimmune pathogenesis (74). These nucleosomes can induce DC maturation in vitro and trigger autoantibody production in vivo when administered to mice (74). In patients with arthritis, exosome-associated DEK, DEK autoantibodies, and immune complexes (ICs) have been detected in synovial fluid, with DEK acetylation critically contributing to its antigenicity (73). DEK-containing exosomes may also contribute to joint inflammation by recruiting neutrophils, NK cells, and CD8⁺ T lymphocytes, thereby amplifying inflammatory and immune responses (48).

Table 1

EV-associated molecules from the nucleus and their potential involvement in autoimmune diseases

The presence of EV-associated nuclear autoantigens may be crucial for the progression of autoimmune diseases, suggesting potential new targets for clinical intervention. This process is further complicated by PTMs, such as citrullination, carbamylation, methylation, acetylation, and peroxidation, which contribute to the formation of neoantigens in EVs that can break immune tolerance (7, 73, 75). However, while these nuclear autoantigens, including DNA, citrullinated histones (75) and lamin B (30, 31) are clearly presented in the released NETs, it remains unclear whether EVs released from NETotic neutrophils also carry them.

Beyond nuclear autoantigens, EVs can also transport cytoplasmic components with autoantigenic properties (76–79) (Table 2). In patients with rheumatoid arthritis (RA), platelet MVs in synovial fluid can transport autoantigenic citrullinated vimentin and fibrinogen, which can form ICs with anti-citrullinated peptide antibodies, potentially amplifying synovial inflammation via neutrophil activation and leukotriene production (76). Similarly, another study reported that synovial exosomes from patients with RA carry citrullinated fibrin-derived peptide autoantigens (79). These findings position EVs as pivotal players in RA pathogenesis by delivering immunogenic citrullinated autoantigens (76, 79). Patients with SLE demonstrate elevated levels of circulating galectin-3–binding protein⁺ (G3BP⁺) MVs, which colocalize with ICs in renal tissues (78), suggesting their direct contribution to lupus nephritis pathogenesis through promoting renal IC deposition. Patients with antineutrophil cytoplasmic antibody–associated vasculitis show elevated levels of circulating proteinase 3 (PR3) autoantigen (80), which also present in neutrophil-derived MVs (77), implicating EVs in autoantigen dissemination and disease pathogenesis. Together, these clinical and experimental findings underscore the importance of EV-associated cytoplasmic autoantigens in driving autoimmunity and disease progression by breaking immune tolerance and promoting pathogenic autoantibody production (Figure 2).

Table 2

EV-associated molecules from cytoplasmic milieu and their potential involvement in autoimmune diseases

EV-associated proteases and proteasomes in antigen presentation. Emerging evidence demonstrates that EVs can modulate antigen presentation. Platelet EVs from human blood have been found to carry proteasomes that can process proteins for antigen presentation to CD8⁺ T cells in mice (39), highlighting their contribution to adaptive immunity. Furthermore, apoptotic exosomes containing 20S proteasome complexes have been shown to regulate autoantibody production through proteasome-mediated degradation, contributing to allograft rejection in mice (81). Cytoplasmic thimet oligopeptidase (TOP) regulates autoimmunity by degrading intracellular antigenic peptides (82), thereby modulating MHC-I antigen presentation and T cell activation (83). Interestingly, TOP retains its enzymatic activity when released via EVs (84, 85), implying its potential role in EV-mediated antigen processing and immune modulation. Moreover, dipeptidyl peptidase IV (DPP-IV), known to promote T cell activation via CD86 upregulation on APCs (86), has been identified in human EVs (87, 88), suggesting its potential involvement in autoimmune pathogenesis (89). Further studies are required to fully elucidate the mechanistic roles of EV-associated proteasomes, TOP, and DPP-IV, and their therapeutic potential (Figure 2 and Table 2).

Beyond antigen processing, exosomes/MVs from APCs can activate T cells in experimental mice by directly presenting antigens to them via MHC-I, MHC-II, and the costimulatory molecules CD80 and CD86 (49, 62) (Figure 3). These EVs also mediate intercellular transfer of functional peptide-MHC complexes between DCs, efficiently activating antigen-specific naive CD4⁺ T cells in mice when administered in vivo (49). MHC-II–bearing EVs from antigen-presenting B cells have been shown to activate CD4⁺ T cells, promoting autoimmunity by driving effector T cell differentiation, B cell proliferation, and immunoglobulin class-switching (62). Conversely, exosomes from activated T cells carry TCR/CD3 complex and adhesion molecules, enabling them to facilitate intercellular communication and signal delivery to cells that express peptide-MHC complexes (90) (Table 3).

Table 3

EV-associated molecules from the plasma membrane and extracellular milieu and their roles in autoimmune diseases

Whereas classical T cell activation requires direct cell-to-cell contact (5, 91), a bidirectional EV-mediated exchange between APCs and T cells represents a distinct, noncanonical pathway for immune communication. Notably, EV-mediated T cell activation may not fully replicate the sustained, highly coordinated signaling of the classical immunological synapse (5). Nevertheless, this process potently modulates immune responses by amplifying antigen-specific signals and disseminating information to multiple T cells or neighboring APCs. Thus, EVs play a nuanced regulatory role, complementing rather than replacing conventional T cell activation.

Tregs are essential for immune tolerance and preventing autoimmune diseases (92). Treg-derived exosomes from human plasma or cell cultures carry ecto-5′-nucleotidase enzyme CD73, which generates immunosuppressive adenosine (63, 93). Moreover, Treg-derived EVs may mediate T cell suppression in vivo by transporting immunosuppressive IL-35, which can coat bystander lymphocytes and lead to their exhaustion (94). Treg-EVs can also mediate immune suppression by transferring specific microRNAs, including miR-150-5p and miR-142-3p, which induce tolerogenic DCs by modulating their IL-10 and IL-6 release (95). In patients with multiple sclerosis, Treg-EVs demonstrate impaired immunosuppressive function compared with those from healthy individuals, a deficit attributed to their reduced miR-142-3p content (96). In mice, Treg-derived exosomes carrying Let-7d miRNA have been shown to suppress Th1 cell proliferation and cytokine secretion in vivo, thereby mitigating systemic inflammation, contributing to suppression and prevention of systemic diseases (97).

Th17 cells oppose Tregs by promoting inflammation in autoimmune disorders. The Treg/Th17 balance maintains immune homeostasis, while its disruption drives autoimmunity (98, 99). Administration of EVs from TGF-β–induced Tregs (100) or gingival mesenchymal stem cells (MSCs) (64) has been shown to improve arthritis in mice by suppressing T cell proliferation and restoring Th17/Treg balance via transferring miR-449a-5p (100) or miR-148a-3p (64), respectively. Similarly, human bone marrow MSC-EVs (65) can improve periodontitis by restoring the Th17/Treg balance in mice via miR-1246 (65). Moreover, labial gland MSC-derived EVs can attenuate experimental Sjögren’s syndrome (SS) in mice by modulating Th17/Treg balance through miRNA let-7f-5p (101), offering a promising target-driven approach for the treatment of SS.

All of the above studies indicate that Treg-EVs and MSC-EVs may mediate immune regulation by transferring key components, including CD73, IL-35, and various immunomodulatory miRNAs, to T cells or DCs, thereby suppressing T cell activity or restoring Th17/Treg balance (Tables 2 and 3).

Inflammation plays a critical role in sustaining autoimmune responses and mediating end-organ damage in autoimmune diseases. EVs transport inflammatory cargo, including nuclear and cytoplasmic DAMPs, cytokines, and other mediators, driving autoimmune inflammation (14, 102–111). EVs carrying membrane cargo may either promote or suppress inflammation (112–115). Additionally, EVs can incorporate extracellular molecules to form a protein corona that amplifies their inflammatory potential (50, 51, 116).

Studies demonstrate that EVs transport various nuclear DAMPs, including nucleic acids (102–104), HMGB1 (14), S100A9 (105), and histones (117), which can activate innate immune responses (Figure 1). EVs from activated macrophages transport nuclear HMGB1 (14), and blood from patients with SLE contains HMGB1-associated nucleosomes (74), which have been shown to stimulate DCs and macrophages, thereby amplifying cytokine production and autoimmune responses in mice (74). Additionally, intraperitoneal injection of histone-containing EVs from P. gingivalis–infected macrophages can induce lung inflammation and alveolar destruction in mice (117), indicating their role in remote inflammatory responses. These in vivo findings suggest that EV-associated HMGB1 and histones are critical pathogenic drivers of systemic inflammation and immune dysregulation (74, 118).

EVs can carry host-derived nuclear DNA (60), which can trigger pDCs (67) or macrophages (119) to produce IFN-I and other cytokines. Emerging evidence reveals they also transport microbial-derived DNA (120–122), highlighting their importance in host-microbiome interactions in autoimmune pathogenesis. Virus-infected cells release EVs containing viral DNA/RNA, triggering various immune responses. Exosomes from hepatitis B/C virus–infected (HBV/HCV-infected) cells can stimulate NK cells or pDCs to produce IFN-γ (102) or IFN-I (103), respectively. Similarly, exosomes from latent Epstein-Barr virus–infected (EBV-infected) B cells contain small RNAs that trigger DCs to produce IFN-β (104). Additionally, EV-packaged bacterial DNA can be delivered to cells, triggering stimulator of interferon genes–mediated (STING-mediated) IFN-I production in mice (123). This mechanism extends to the gut microbiota, where EV-transported microbial DNA can enter the circulation and drive systemic inflammation in distant organs via the cyclic GMP-AMP synthase (cGAS) and STING pathways (124). Notably, fungal DNA within EVs can activate the STING pathway in macrophages, stimulating IFN-I responses (125). The delivery of immunostimulatory nucleic acids via EVs provides a clinically relevant mechanism that bridges common environmental triggers (e.g., infection, cellular damage) to the breakdown of self-tolerance (Table 1).

Therefore, by transporting nuclear DAMPs alongside host and microbial DNA/RNAs, EVs serve as a central link between PCD, host-pathogen interactions, and the initiation of autoimmunity, driving the inflammatory responses that sustain autoimmune pathogenesis.

Normally confined within cells, cytoplasmic DAMPs, like mtDNA (106), HSPs (111), and inflammasome components (109), can be packaged into EVs (Figure 2). Exosomes carrying mtDNA from human blood can stimulate proinflammatory cytokine production, including IL-1β release from microglia (106) and monocytes (126). Additionally, oxidized mtDNA-carrying exosomes from activated T cells have been shown to trigger IFN-I production in DCs via antigen-specific interactions (127). Furthermore, EVs with mitochondrial antiviral signaling protein (MAVS) can also stimulate DCs to produce IFN-β (110). Under cellular stress, cytoplasmic HSP70 translocates to the plasma membrane (128) and is subsequently released with EVs (111). EV-associated HSP70 is 260-fold more effective than free recombinant HSP70 in inducing macrophage TNF-α production in vitro (111), suggesting that membrane-dependent EV delivery significantly enhances HSP70 immunostimulatory capacity (111). HSP70-containing EVs can suppress tumor progression in melanoma and colon carcinoma mouse models by promoting antitumor cytokine (IL-10, TNF-α, and IFN-γ) production and enhancing NK cell activity (129), indicating their role in immunomodulatory and inflammatory responses. Additionally, microglia-derived exosomes can transport apoptosis-associated speck-like protein containing a CARD (ASC), which can induce inflammasome activation and IL-1β production in vitro and in vivo (109).

Contrary to the traditional view of cytokines as freely diffusible molecules, several studies have reported that some cytokines can be transported by EVs, including IL-1β (107) and TNF-α (108). A systematic analysis further identified up to 33 cytokines associated with EVs that can functionally activate target cells (46). By serving as mobile cytokine reservoirs, EVs enhance cytokine stability and enable targeted delivery to distant tissues. EVs that are engineered and loaded with specific cytokines to precisely modulate immunity could offer significant clinical advantages over freely diffusible cytokines (46, 130) (Table 2).

EVs transport diverse membrane molecules that exhibit multiple roles (112–115) (Figure 3). CD40 ligand–bearing (CD40L-bearing) EVs have been shown to promote liver inflammation in vivo by triggering macrophage cytokine production (113), while EVs carrying oxidized membrane lipids can induce endothelial activation and vascular inflammation (131). In RA, leukocyte EVs may amplify synovial inflammation by transferring arachidonic acid to fibroblasts, thus driving proinflammatory prostaglandin E2 production (112). Conversely, PS/annexin A1–bearing neutrophil MVs from patients with RA have demonstrated antiarthritic effects in mice by suppressing macrophage activation and promoting TGF-β production (115). Furthermore, PS-exposing EVs have been reported to promote CD8⁺ T cell proliferation and potentiate antiviral immunity in mice, suggesting their therapeutic potential for augmenting adaptive immunity against viral infections (114).

Beyond their intrinsic cargo, MVs may incorporate extracellular components on their surface, including complement (C1q/C3/C4), C-reactive protein (CRP), serum amyloid P (SAP), and immunoglobulins (IgM/IgG) (50). In patients with RA, synovial fluid EVs show significantly higher levels of C1q/C3/C4 than plasma-derived EVs, indicating localized activation of the classical complement pathway within affected joints (50). Similarly, patients with SLE exhibit elevated circulating levels of complement-bearing MVs compared with healthy controls (116). Emerging research reveals that EVs can dynamically form a functional protein corona by incorporating diverse extracellular molecules from surrounding biological fluids — including complement, apolipoproteins A1/B/C3/E, and fibrinogen (51). These corona proteins can enhance EV immunomodulatory functions by boosting DC cytokine production (51), amplifying EVs’ potential to regulate immune responses (132), and facilitating EV-immune cell interactions (133) (Table 3).

Originally proposed a century ago, the immune surveillance concept postulated that the immune system constantly identifies and eliminates potentially cancerous cells (17, 134). Although initially doubted owing to a lack of evidence, this concept is now widely accepted, and the elevated cancer incidence in immunodeficient humans and mice (134) underscores the critical role of the immune system in controlling oncogenesis. Moreover, this fundamental mechanism is not limited to cancer but extends to a broad spectrum of pathological conditions — including autoimmune disorders, infection, aging, and tissue injury (18–20, 135–140).

The innate immune system, including macrophages and DCs, plays a key role in immune surveillance by continuously detecting tumor-associated antigens (TAAs) (17, 141, 142). These professional APCs process and present TAA fragments to T cells, initiating adaptive immune responses that lead to cancer cell elimination by cytotoxic T cells (17, 141, 142). Furthermore, NK cells contribute to antitumor immunity by eliminating “missing-self” cancer cells that have downregulated TAAs (141), while macrophages can directly destroy cancer cells via phagocytosis (141). Understanding of this foundational mechanism has driven advances of cancer immunotherapies, including chimeric antigen receptor (CAR) T cell therapy (143).

In autoimmune diseases, defective clearance of cells undergoing PCD results in accumulation of immunogenic debris. APCs take up the debris and present self-antigens to T cells, triggering autoreactive T cells to target altered self-cells, which cause tissue damage and autoimmune pathogenesis (18, 144). This process mirrors tumor surveillance (17, 142), where the failed clearance of mutated cells enables tumorigenesis (17, 134). The fundamental distinction is that inadequate immune surveillance allows cancer growth, whereas excessive immune activity targeting altered-self tissues drives autoimmune pathogenesis (Table 4) (7,18,140). Interestingly, patients with autoimmune diseases have an elevated risk of developing certain cancers (145), and cancer immunotherapies may trigger autoimmune conditions (146), which in some cases are paradoxically linked to a better cancer prognosis (147). Furthermore, the effectiveness of CAR T therapy in treating B cell malignancies (19) and SLE (148) has sparked interest in targeting autoreactive B cells to treat other autoimmune diseases. This evidence suggests that autoimmunity and cancer are interconnected, both stemming from dysregulated immune homeostasis (149), and share some common components of immune surveillance mechanisms (Table 4).

Table 4

Immune surveillance in cancer versus autoimmune diseases

The recently proposed autoimmune surveillance of hypersecreting mutants hypothesis (18) suggests that autoreactive T cells can help maintain endocrine homeostasis by eliminating hyperactive endocrine cells, implying that autoimmunity may result from a dysregulation of this surveillance process (140). This concept extends to EVs and their cargo, which have been implicated in multiple aspects of immune regulation and surveillance (2, 7, 141, 142).

Like TAAs, EV-associated nuclear autoantigens can be recognized by APCs (60, 67, 127), which, in turn, release cytokines and activate T cells (66, 127, 144). Notably, damaged nuclear DNA, sequestered in micronuclei (45), can be packaged into EVs (43, 44). Upon release, the EV-associated DNA can be recognized as “foreign” by immune cells through cytosolic surveillance sensors, including the cGAS and STING pathways critical for immune surveillance in both cancer and autoimmune diseases (144, 150, 151). Through in vitro and in vivo studies, Mackenzie and colleagues demonstrated that rupture of the micronuclear envelope leads to rapid cGAS recruitment, alerting the cytosolic surveillance sensor and producing IFN-I (150), a key player in autoimmune diseases like SLE. This research suggests that a breakdown in this specific pathway — which is meant to protect cells from foreign DNA — could be a primary trigger for autoimmune diseases.

When nuclear HMGB1 is released from cancer cells, it can initiate an autocrine signaling loop that upregulates immunosuppressive galectin-9, which inhibits NK and T cell antitumor activity and enables the cancer cells to evade immune surveillance (152). HMGB1, which can also be released via EVs (14), has been shown to impair immune surveillance by inhibiting macrophage phagocytic clearance of apoptotic cells through PS binding (153), leading to accumulation of immunogenic cell debris and PCD-derived EVs. Furthermore, HMGB1 can enhance DC uptake of extracellular DNA, thereby promoting cGAS-STING activation and amplifying IFN-I production (154). Thereby, EV-associated nuclear DNA and HMGB1 may contribute to autoimmune diseases (2, 7, 155) by modulating cytosolic surveillance (150) and interfering with dead cell clearance (153), although further research is needed to understand the precise role of nuclear cargo-carrying EVs in autoimmune surveillance and pathogenesis.

Emerging evidence indicates that EVs may play a regulatory role in immune surveillance by modulating cytotoxic T cell and NK cell activity (156). Human NK cell–derived exosomes from blood carry cytoplasmic perforin and granulysin (157–159), which can kill tumor cells (157, 158) and activate T cells (157, 158) in vitro, indicating their potential involvement in immune surveillance. Moreover, NK cell–derived EVs have been shown to shuttle microRNAs that enhance T cell activation and promote monocyte differentiation into DCs with upregulated MHC-II/CD86 expression, thereby increasing their antigen presentation capacity (160). Notably, delivering NK-EVs enriched with specific miRNAs (miR-10b-5p, miR-92a-3p, and miR-155-5p) to mice can recapitulate these immunomodulatory effects on T cell responses (160). Furthermore, Treg-derived EVs can transport immunomodulatory miRNAs that suppress T cell and DC activation (95, 96, 161), demonstrating their potential role in maintaining immune tolerance and surveillance.

EVs carrying both mtDNA and PD-L1 have been shown to promote tumor progression in mice by shaping an immunosuppressive tumor microenvironment with IFN-I and IL-6 production from macrophages, while simultaneously suppressing T cell immunity (162). Notably, EVs carrying STING oligomers have been reported to suppress innate immune responses, serving as a negative feedback mechanism to prevent STING pathway overactivation (163). However, intratumoral injection of STING agonist–loaded EVs in mice can potently enhance antitumor immune surveillance by stimulating CD8⁺ T cell activation and IFN-I production (164). Therefore, EVs play a complex, context-dependent role in regulating STING signaling.

Exposed on apoptotic cells and MVs (7, 165), PS serves as an “eat-me” signal for macrophage phagocytosis (166). This process is essential for maintaining immune homeostasis, playing a critical role in promoting antitumor immunity (167, 168) and preserving immune tolerance (169, 170) (Table 4). Disruption of this process — due to excessive apoptosis, dysregulated PS exposure on tumors, or elevated levels of PS⁺ EVs — can overwhelm immunosurveillance, enabling tumor evasion and progression (167, 168) or breaking immune tolerance and triggering autoimmunity (170). In SLE, PS-bearing MVs may competitively inhibit macrophage phagocytosis of apoptotic cells (171), resulting in impaired clearance of dying cells (172) and a loss of immune tolerance. Interestingly, recent research has reported that PS⁺ EVs can directly bind to and activate CD8⁺ T cells, driving their differentiation and proliferation during antiviral immune surveillance in mice (114). Thus, dysregulation of PS⁺ EVs may contribute to autoimmune pathogenesis both by impairing macrophage-dependent clearance of immunogenic dead cell debris and by promoting autoreactive T cell responses.

The CD47–signal-regulatory protein α (SIRPα) interaction serves as a critical phagocytosis checkpoint, where CD47-expressing cells deliver a “don’t-eat-me” signal through SIRPα on myeloid cells to maintain immune homeostasis (173). This pathway has significant clinical implications, as CD47 enables both tumor (174) and apoptotic (139) cells to evade immune surveillance. Therapeutic blockade of CD47 enhances phagocytic clearance and demonstrates protective effects in murine models of autoimmune encephalomyelitis (175) and lupus nephritis (176). Pathologically, CD47-carrying exosomes can contribute to disease progression by suppressing macrophage-mediated clearance of apoptotic or cancer cells (177), thereby exacerbating autoimmune pathogenesis (175, 176) and promoting tumor immune evasion (177). Leveraging these immune-evasive properties, CD47-bearing EVs have been used for the targeted delivery of cyclosporin A/miR inhibitors, protecting mice from hepatic ischemia/reperfusion injury (135). This highlights their potential as a sophisticated tool for precisely modulating immune surveillance in a clinical setting.

The PD-1/PD-L1 axis is a critical immune checkpoint that delivers “don’t-kill-me” inhibitory signals to regulate T cell responses and maintain immune tolerance. The clinical importance of this pathway is highlighted by the development of lupus-like autoimmunity in PD-1–deficient mice, which exhibit uncontrolled T cell activity (178). In oncology, PD-L1–bearing exosomes or EVs from patients with melanoma (179) or glioblastoma (180) have been shown to mediate immune evasion by suppressing antitumor T cells. Similarly, in mice PD-L1–bearing EVs promote tumor progression (162). In an autoimmune context, higher levels of PD-L1–bearing β cell–derived EVs correlate with a greater number of remaining β cells in patients with type 1 diabetes, suggesting a protective role in preserving β cell mass, as these EVs have been shown to inhibit CD8⁺ T cell activity in vitro (181). PD-L1–expressing MSC-EVs exhibit suppressive effects on T cell activation and ameliorate psoriatic inflammation in mouse models (182).

Furthermore, CD73-carrying EVs from Tregs have been shown to suppress T cell proliferation by generating immunosuppressive adenosine (63, 93). Exosomes from tumor cells and those circulating in the blood of patients with cancer carry NKG2D ligands that have been shown to suppress NK and CD8⁺ T cell cytotoxicity by downregulating NKG2D, enabling cancer cells to evade immune surveillance (183, 184). The clinical significance of this pathway is highlighted by the detection of NKG2D ligand⁺ MVs in the bone marrow of patients with multiple myeloma (185), suggesting their pivotal role in creating an immunosuppressive microenvironment that favors tumor growth. Additionally, EVs can also modulate immune surveillance by interacting with the complement system (186), which is often associated with the EV protein corona (50, 51).

In summary, emerging evidence indicates that EVs may regulate immune surveillance through multiple mechanisms, such as (a) activating cytosolic surveillance sensors (150, 151, 187), (b) modulating immune checkpoints (179, 180, 188), (c) regulating NK/T cell cytotoxicity (152, 156), and (d) influencing macrophage and DC phagocytic clearance (171, 172, 175, 176). Notably, the field remains critically underexplored. Further research into immune surveillance in autoimmune diseases and the involvement of EVs is required to pave the way for innovative therapeutic strategies against immune dysregulation.

As potential mediators linking cellular processes and autoimmune pathogenesis, EVs are recognized to transport cargo from distinct subcellular compartments, contributing to disease progression by delivering immunogenic molecules, regulating antigen processing and presentation, and modulating various immune responses. EVs can fuel inflammation by carrying proinflammatory mediators, sustaining autoimmune responses and promoting end-organ damage. Emerging evidence also suggests that EVs might regulate immune surveillance by influencing cytosolic sensors, immune checkpoints, NK/T cell cytotoxicity, and macrophage/DC phagocytic activity. However, the precise role of EV-mediated immune surveillance in maintaining immune homeostasis and driving autoimmunity remains a critical frontier for further research, requiring rigorous basic and clinical investigation to delineate the characteristics of autoimmunity from those observed over the past decades in cancer biology.

Despite significant progress over the past decades, EV research continues to face considerable technical hurdles in functional studies and establishing causality. The general advantages, disadvantages, and technical challenges in EV research have been thoroughly discussed elsewhere (189). In this Review, we focused on emerging mechanistic and translational findings to highlight critical knowledge gaps in the context of autoimmune diseases. Although existing studies have employed a variety of EV isolation and detection techniques (Tables 1–3), key issues remain in EV functional studies, including (a) contamination by nonvesicular particles, (b) inherent complexity due to EV population heterogeneity, and (c) a general lack of mechanistic proof with correlation studies (Table 5). Future studies must adopt standardized methodologies (i.e., MISEV2023) (189) and incorporate rigorous in vivo validation — specifically tackling key challenges, such as distinguishing EV effects from parental cell activities, controlling for intervention off-target effects, and improving our limited understanding of EV pharmacokinetics and biodistribution in different organs (Table 5). To establish robust causal conclusions, strategies like selectively blocking EV production, interrupting EV uptake in vivo, or performing cargo-specific modifications could be employed. Furthermore, high-throughput techniques like proteomics, RNA sequencing, and time-of-flight mass spectrometry will be helpful for translating findings from the bench to the bedside.

Table 5

Major challenges in EV functional studies and causality investigations in vivo

Key knowledge gaps in our understanding of EV biology still remain, including, but not limited to, the regulation of EV biogenesis, selective cargo sorting, and the content-dependent effects of EVs on various immune responses. This is further complicated by the dual pro- and antiinflammatory roles of EVs, which means their effects are highly dependent on context. These complexities necessitate the development of tailored therapeutic strategies for future clinical applications. Beyond targeting natural EVs, engineered EVs have emerged as promising platforms for targeted therapy. As discussed elsewhere (190, 191), significant translational hurdles remain for EV-based therapeutics, including scalable production, storage and in vivo stability, appropriate dosing, and managing their immunogenicity and potential to disrupt immune balance. All of these challenges need to be addressed for successful clinical use. Despite these obstacles, EV research holds great promise for advancing our mechanistic understanding of autoimmune pathogenesis and fostering the development of innovative therapeutic strategies.

MLL, WW, and XW conceived the concepts and designed the study. XW, YL, YZ, WW, and MLL drafted the first version of the manuscript. YZ, XL, XW, YL, NZ, WW, and MLL critically revised and finalized the manuscript. All authors critically contributed important intellectual content to the manuscript.

• NIH (grant R21AI144838).
• Lupus Research Alliance (grant 416805).

The authors would like to acknowledge departmental colleagues for their help in the preparation of this work.

Address correspondence to: Wei Wei, Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300020, China. Email: tjweiwei2003@163.com. Or to: Ming-Lin Liu, Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. Email: lium1@pennmedicine.upenn.edu.

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2026, Zhao et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2026;136(3):e194715. https://doi.org/10.1172/JCI194715.

1. Wu X, et al. Extracellular vesicles in autoimmune vasculitis - Little dirts light the fire in blood vessels. Autoimmun Rev. 2019;18(6):593–606.
   View this article via: CrossRef PubMed Google Scholar
2. Zhao Y, et al. Extracellular vesicles and lupus nephritis - New insights into pathophysiology and clinical implications. J Autoimmun. 2020;115:102540.
   View this article via: CrossRef PubMed Google Scholar
3. Rajendran L, et al. Lipid-anchored drugs for delivery into subcellular compartments. Trends Pharmacol Sci. 2012;33(4):215–222.
   View this article via: CrossRef PubMed Google Scholar
4. Diekmann Y, Pereira-Leal JB. Evolution of intracellular compartmentalization. Biochem J. 2013;449(2):319–331.
   View this article via: CrossRef PubMed Google Scholar
5. van Niel G, et al. Challenges and directions in studying cell-cell communication by extracellular vesicles. Nat Rev Mol Cell Biol. 2022;23(5):369–382.
   View this article via: CrossRef PubMed Google Scholar
6. Horwitz DA, et al. Rebalancing immune homeostasis to treat autoimmune diseases. Trends Immunol. 2019;40(10):888–908.
   View this article via: CrossRef PubMed Google Scholar
7. Liu ML, et al. Microvesicles in autoimmune diseases. Adv Clin Chem. 2016;77:125–175.
   View this article via: PubMed Google Scholar
8. Lázaro-Ibáñez E, et al. DNA analysis of low- and high-density fractions defines heterogeneous subpopulations of small extracellular vesicles based on their DNA cargo and topology. J Extracell Vesicles. 2019;8(1):1656993.
   View this article via: CrossRef PubMed Google Scholar
9. Buzas EI. The roles of extracellular vesicles in the immune system. Nat Rev Immunol. 2023;23(4):236–250.
   View this article via: CrossRef PubMed Google Scholar
10. Mori MA, et al. Extracellular miRNAs: from biomarkers to mediators of physiology and disease. Cell Metab. 2019;30(4):656–673.
    View this article via: CrossRef PubMed Google Scholar
11. Roefs MT, et al. Extracellular vesicle-associated proteins in tissue repair. Trends Cell Biol. 2020;30(12):990–1013.
    View this article via: CrossRef PubMed Google Scholar
12. Joshi BS, et al. Endocytosis of extracellular vesicles and release of their cargo from endosomes. ACS Nano. 2020;14(4):4444–4455.
    View this article via: CrossRef PubMed Google Scholar
13. Amari L, Germain M. Mitochondrial extracellular vesicles - origins and roles. Front Mol Neurosci. 2021;14:767219.
    View this article via: CrossRef PubMed Google Scholar
14. Chen Y, et al. Translocation of endogenous danger signal HMGB1 from nucleus to membrane microvesicles in macrophages. J Cell Physiol. 2016;231(11):2319–2326.
    View this article via: CrossRef PubMed Google Scholar
15. van der Pol E, et al. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64(3):676–705.
    View this article via: CrossRef PubMed Google Scholar
16. Ricco C, et al. Extracellular vesicles in the pathogenesis, clinical characterization, and management of dermatomyositis: a narrative review. Int J Mol Sci. 2024;25(4):1967.
    View this article via: CrossRef PubMed Google Scholar
17. Ribatti D. The concept of immune surveillance against tumors. The first theories. Oncotarget. 2017;8(4):7175–7180.
    View this article via: CrossRef PubMed Google Scholar
18. Korem Kohanim Y, et al. Endocrine autoimmune disease as a fragility of immune surveillance against hypersecreting mutants. Immunity. 2020;52(5):872–884.
    View this article via: CrossRef PubMed Google Scholar
19. Muller F, et al. CD19 CAR T-cell therapy in autoimmune disease - a case series with follow-up. N Engl J Med. 2024;390(8):687–700.
    View this article via: CrossRef PubMed Google Scholar
20. Kupper TS, Fuhlbrigge RC. Immune surveillance in the skin: mechanisms and clinical consequences. Nat Rev Immunol. 2004;4(3):211–222.
    View this article via: CrossRef PubMed Google Scholar
21. Russell AE, et al. Biological membranes in EV biogenesis, stability, uptake, and cargo transfer: an ISEV position paper arising from the ISEV membranes and EVs workshop. J Extracell Vesicles. 2019;8(1):1684862.
    View this article via: CrossRef PubMed Google Scholar
22. Kowal J, et al. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116–125.
    View this article via: CrossRef PubMed Google Scholar
23. Shi B, et al. Extracellular vesicles from the dead: the final message. Trends Cell Biol. 2025;35(5):439–452.
    View this article via: CrossRef PubMed Google Scholar
24. Yanez-Mo M, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015;4:27066.
    View this article via: CrossRef PubMed Google Scholar
25. Ito F, et al. Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin. Redox Biol. 2021;47:102174.
    View this article via: CrossRef PubMed Google Scholar
26. Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2019;26(1):99–114.
    View this article via: CrossRef PubMed Google Scholar
27. Zargarian S, et al. Phosphatidylserine externalization, “necroptotic bodies” release, and phagocytosis during necroptosis. PLoS Biol. 2017;15(6):e2002711.
    View this article via: CrossRef PubMed Google Scholar
28. Raden Y, et al. Necroptotic extracellular vesicles - present and future. Semin Cell Dev Biol. 2021;109:106–113.
    View this article via: CrossRef PubMed Google Scholar
29. Li M, et al. Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation. Theranostics. 2022;12(5):2133–2149.
    View this article via: CrossRef PubMed Google Scholar
30. Li Y, et al. Nuclear envelope rupture and NET formation is driven by PKCα-mediated lamin B disassembly. EMBO Rep. 2020;21(8):e48779.
    View this article via: CrossRef PubMed Google Scholar
31. Liu ML, et al. Recent progress in the mechanistic understanding of NET formation in neutrophils. FEBS J. 2022;289(14):3954–3966.
    View this article via: CrossRef PubMed Google Scholar
32. Chen X, et al. Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021;218(6):e20210518.
    View this article via: CrossRef PubMed Google Scholar
33. Meng Q, et al. Interrelation between programmed cell death and immunogenic cell death: take antitumor nanodrug as an example. Small Methods. 2023;7(5):e2201406.
    View this article via: CrossRef PubMed Google Scholar
34. Galluzzi L, et al. Immunogenic cell death in cancer: concept and therapeutic implications. J Transl Med. 2023;21(1):162.
    View this article via: CrossRef PubMed Google Scholar
35. Hurley JH, et al. Membrane budding. Cell. 2010;143(6):875–887.
    View this article via: CrossRef PubMed Google Scholar
36. Tekpli X, et al. Role for membrane remodeling in cell death: implication for health and disease. Toxicology. 2013;304:141–157.
    View this article via: CrossRef PubMed Google Scholar
37. Moudgil KD, Sercarz EE. Understanding crypticity is the key to revealing the pathogenesis of autoimmunity. Trends Immunol. 2005;26(7):355–359.
    View this article via: CrossRef PubMed Google Scholar
38. Starck SR, Shastri N. Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance. Immunol Rev. 2016;272(1):8–16.
    View this article via: CrossRef PubMed Google Scholar
39. Marcoux G, et al. Platelet EVs contain an active proteasome involved in protein processing for antigen presentation via MHC-I molecules. Blood. 2021;138(25):2607–2620.
    View this article via: CrossRef PubMed Google Scholar
40. Singh J, et al. Moonlighting chromatin: when DNA escapes nuclear control. Cell Death Differ. 2023;30(4):861–875.
    View this article via: CrossRef PubMed Google Scholar
41. Panagaki D, et al. Nuclear envelope budding is a response to cellular stress. Proc Natl Acad Sci U S A. 2021;118(30):e2020997118.
    View this article via: CrossRef PubMed Google Scholar
42. Sule KC, et al. Nuclear envelope budding: Getting large macromolecular complexes out of the nucleus. Bioessays. 2024;46(2):e2300182.
    View this article via: CrossRef PubMed Google Scholar
43. Elzanowska J, et al. DNA in extracellular vesicles: biological and clinical aspects. Mol Oncol. 2021;15(6):1701–1714.
    View this article via: CrossRef PubMed Google Scholar
44. Yokoi A, et al. Mechanisms of nuclear content loading to exosomes. Sci Adv. 2019;5(11):eaax8849.
    View this article via: CrossRef PubMed Google Scholar
45. Gekara NO. DNA damage-induced immune response: Micronuclei provide key platform. J Cell Biol. 2017;216(10):2999–3001.
    View this article via: CrossRef PubMed Google Scholar
46. Fitzgerald W, et al. A system of cytokines encapsulated in extracellular vesicles. Sci Rep. 2018;8(1):8973.
    View this article via: CrossRef PubMed Google Scholar
47. Kalra H, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012;10(12):e1001450.
    View this article via: CrossRef PubMed Google Scholar
48. Mor-Vaknin N, et al. The DEK nuclear autoantigen is a secreted chemotactic factor. Mol Cell Biol. 2006;26(24):9484–9496.
    View this article via: CrossRef PubMed Google Scholar
49. Thery C, et al. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol. 2002;3(12):1156–1162.
    View this article via: CrossRef PubMed Google Scholar
50. Biro E, et al. Activated complement components and complement activator molecules on the surface of cell-derived microparticles in patients with rheumatoid arthritis and healthy individuals. Ann Rheum Dis. 2007;66(8):1085–1092.
    View this article via: CrossRef PubMed Google Scholar
51. Toth EA, et al. Formation of a protein corona on the surface of extracellular vesicles in blood plasma. J Extracell Vesicles. 2021;10(11):e12140.
    View this article via: CrossRef PubMed Google Scholar
52. Mir B, Goettsch C. Extracellular vesicles as delivery vehicles of specific cellular cargo. Cells. 2020;9(7):1601.
    View this article via: CrossRef PubMed Google Scholar
53. Anderson HA, et al. Concentration of MHC class II molecules in lipid rafts facilitates antigen presentation. Nat Immunol. 2000;1(2):156–162.
    View this article via: CrossRef PubMed Google Scholar
54. Sapon K, et al. The role of lipid rafts in vesicle formation. J Cell Sci. 2023;136(9):jcs260887.
    View this article via: CrossRef PubMed Google Scholar
55. Yanez-Mo M, et al. Tetraspanin-enriched microdomains: a functional unit in cell plasma membranes. Trends Cell Biol. 2009;19(9):434–446.
    View this article via: CrossRef PubMed Google Scholar
56. Andreu Z, Yanez-Mo M. Tetraspanins in extracellular vesicle formation and function. Front Immunol. 2014;5:442.
    View this article via: CrossRef PubMed Google Scholar
57. Perez-Boza J, et al. hnRNPA2B1 inhibits the exosomal export of miR-503 in endothelial cells. Cell Mol Life Sci. 2020;77(21):4413–4428.
    View this article via: CrossRef PubMed Google Scholar
58. Carnino JM, et al. Post-translational modification regulates formation and cargo-loading of extracellular vesicles. Front Immunol. 2020;11:948.
    View this article via: CrossRef PubMed Google Scholar
59. Soni C, Reizis B. DNA as a self-antigen: nature and regulation. Curr Opin Immunol. 2018;55:31–37.
    View this article via: CrossRef PubMed Google Scholar
60. Sisirak V, et al. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell. 2016;166(1):88–101.
    View this article via: CrossRef PubMed Google Scholar
61. Kapsogeorgou EK, et al. Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins. Arthritis Rheum. 2005;52(5):1517–1521.
    View this article via: CrossRef PubMed Google Scholar
62. Lindenbergh MFS, Stoorvogel W. Antigen presentation by extracellular vesicles from professional antigen-presenting cells. Annu Rev Immunol. 2018;36:435–459.
    View this article via: CrossRef PubMed Google Scholar
63. Smyth LA, et al. CD73 expression on extracellular vesicles derived from CD4+ CD25+ Foxp3+ T cells contributes to their regulatory function. Eur J Immunol. 2013;43(9):2430–2440.
    View this article via: CrossRef PubMed Google Scholar
64. Chen J, et al. miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model. JCI Insight. 2024;9(10):e177841.
    View this article via: JCI Insight CrossRef PubMed Google Scholar
65. Xia Y, et al. Human bone marrow mesenchymal stem cell-derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR-1246. FASEB J. 2023;37(11):e23226.
    View this article via: CrossRef PubMed Google Scholar
66. Maione F, et al. Chicken-or-egg question: Which came first, extracellular vesicles or autoimmune diseases? J Leukoc Biol. 2020;108(2):601–616.
    View this article via: CrossRef PubMed Google Scholar
67. Lande R, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449(7162):564–569.
    View this article via: CrossRef PubMed Google Scholar
68. Soni C, et al. Plasmacytoid dendritic cells and type i interferon promote extrafollicular B cell responses to extracellular self-DNA. Immunity. 2020;52(6):1022–1038.
    View this article via: CrossRef PubMed Google Scholar
69. Hartl J, et al. Autoantibody-mediated impairment of DNASE1L3 activity in sporadic systemic lupus erythematosus. J Exp Med. 2021;218(5):e20201138.
    View this article via: CrossRef PubMed Google Scholar
70. Nielsen CT, et al. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthritis Rheum. 2012;64(4):1227–1236.
    View this article via: CrossRef PubMed Google Scholar
71. Schiller M, et al. Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis. Cell Death Differ. 2008;15(1):183–191.
    View this article via: CrossRef PubMed Google Scholar
72. Klein B, et al. From the nucleus to the plasma membrane: translocation of the nuclear proteins histone H3 and lamin B1 in apoptotic microglia. Apoptosis. 2014;19(5):759–775.
    View this article via: CrossRef PubMed Google Scholar
73. Mor-Vaknin N, et al. DEK in the synovium of patients with juvenile idiopathic arthritis: characterization of DEK antibodies and posttranslational modification of the DEK autoantigen. Arthritis Rheum. 2011;63(2):556–567.
    View this article via: CrossRef PubMed Google Scholar
74. Urbonaviciute V, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med. 2008;205(13):3007–3018.
    View this article via: CrossRef PubMed Google Scholar
75. Muller S, Radic M. Citrullinated autoantigens: from diagnostic markers to pathogenetic mechanisms. Clin Rev Allergy Immunol. 2015;49(2):232–239.
    View this article via: CrossRef PubMed Google Scholar
76. Cloutier N, et al. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol Med. 2013;5(2):235–249.
    View this article via: CrossRef PubMed Google Scholar
77. Martin KR, et al. Proteinase 3 is a phosphatidylserine-binding protein that affects the production and function of microvesicles. J Biol Chem. 2016;291(20):10476–10489.
    View this article via: CrossRef PubMed Google Scholar
78. Nielsen CT, et al. Galectin-3 binding protein links circulating microparticles with electron dense glomerular deposits in lupus nephritis. Lupus. 2015;24(11):1150–1160.
    View this article via: CrossRef PubMed Google Scholar
79. Skriner K, et al. Association of citrullinated proteins with synovial exosomes. Arthritis Rheum. 2006;54(12):3809–3814.
    View this article via: CrossRef PubMed Google Scholar
80. Ohlsson S, et al. Increased circulating levels of proteinase 3 in patients with anti-neutrophilic cytoplasmic autoantibodies-associated systemic vasculitis in remission. Clin Exp Immunol. 2003;131(3):528–535.
    View this article via: CrossRef PubMed Google Scholar
81. Dieude M, et al. The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci Transl Med. 2015;7(318):318ra200.
    View this article via: CrossRef PubMed Google Scholar
82. Shrimpton CN, et al. Soluble metalloendopeptidases and neuroendocrine signaling. Endocr Rev. 2002;23(5):647–664.
    View this article via: CrossRef PubMed Google Scholar
83. Murata S, et al. The immunoproteasome and thymoproteasome: functions, evolution and human disease. Nat Immunol. 2018;19(9):923–931.
    View this article via: CrossRef PubMed Google Scholar
84. Liu Y, et al. Extracellular vesicles and angiotensin-converting enzyme 2 in COVID-19 disease. BIOCELL. 2024;48(1):1–8.
    View this article via: CrossRef Google Scholar
85. Liu Y, et al. Thimet oligopeptidase—a classical enzyme with new function and new form. Immuno. 2021;1(4):332–346.
    View this article via: CrossRef Google Scholar
86. Ohnuma K, et al. CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1. Proc Natl Acad Sci U S A. 2004;101(39):14186–14191.
    View this article via: CrossRef PubMed Google Scholar
87. Kandzija N, et al. Placental extracellular vesicles express active dipeptidyl peptidase IV; levels are increased in gestational diabetes mellitus. J Extracell Vesicles. 2019;8(1):1617000.
    View this article via: CrossRef PubMed Google Scholar
88. Ogawa Y, et al. Distinguishing two distinct types of salivary extracellular vesicles: a potential tool for understanding their pathophysiological roles. Front Mol Biosci. 2024;11:1278955.
    View this article via: CrossRef PubMed Google Scholar
89. Kim SJ, et al. Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation. Diabetes. 2009;58(3):641–651.
    View this article via: CrossRef PubMed Google Scholar
90. Blanchard N, et al. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol. 2002;168(7):3235–3241.
    View this article via: CrossRef PubMed Google Scholar
91. Busch A, et al. Transfer of T cell surface molecules to dendritic cells upon CD4+ T cell priming involves two distinct mechanisms. J Immunol. 2008;181(6):3965–3973.
    View this article via: CrossRef PubMed Google Scholar
92. Sumida TS, et al. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nat Rev Immunol. 2024;24(7):503–517.
    View this article via: CrossRef PubMed Google Scholar
93. Schuler PJ, et al. Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells. Clin Exp Immunol. 2014;177(2):531–543.
    View this article via: CrossRef PubMed Google Scholar
94. Sullivan JA, et al. Treg-cell-derived IL-35-coated extracellular vesicles promote infectious tolerance. Cell Rep. 2020;30(4):1039–1051.
    View this article via: CrossRef PubMed Google Scholar
95. Tung SL, et al. Regulatory T cell-derived extracellular vesicles modify dendritic cell function. Sci Rep. 2018;8(1):6065.
    View this article via: CrossRef PubMed Google Scholar
96. De Rosa G, et al. MicroRNA-142-3p shuttling in extracellular vesicles marks regulatory T cell dysfunction in multiple sclerosis. Sci Transl Med. 2025;17(800):eadl1698.
    View this article via: CrossRef PubMed Google Scholar
97. Okoye IS, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014;41(1):89–103.
    View this article via: CrossRef PubMed Google Scholar
98. Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014;13(6):668–677.
    View this article via: CrossRef PubMed Google Scholar
99. Wang J, et al. Intricacies of TGF-β signaling in Treg and Th17 cell biology. Cell Mol Immunol. 2023;20(9):1002–1022.
    View this article via: CrossRef PubMed Google Scholar
100. Chen J, et al. TGF-β-induced CD4+ FoxP3+ regulatory T cell-derived extracellular vesicles modulate Notch1 signaling through miR-449a and prevent collagen-induced arthritis in a murine model. Cell Mol Immunol. 2021;18(11):2516–2529.
     View this article via: CrossRef PubMed Google Scholar
101. Xie Y, et al. miRNA let-7f-5p-encapsulated labial gland MSC-derived EVs ameliorate experimental Sjögren’s syndrome by suppressing Th17 cells via targeting RORC/IL-17A signaling axis. J Nanobiotechnology. 2025;23(1):228.
     View this article via: CrossRef PubMed Google Scholar
102. Kouwaki T, et al. Extracellular vesicles including exosomes regulate innate immune responses to hepatitis B virus infection. Front Immunol. 2016;7:335.
     View this article via: CrossRef PubMed Google Scholar
103. Dreux M, et al. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe. 2012;12(4):558–570.
     View this article via: CrossRef PubMed Google Scholar
104. Baglio SR, et al. Sensing of latent EBV infection through exosomal transfer of 5’pppRNA. Proc Natl Acad Sci U S A. 2016;113(5):E587–E596.
     View this article via: CrossRef PubMed Google Scholar
105. New SE, et al. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res. 2013;113(1):72–77.
     View this article via: CrossRef PubMed Google Scholar
106. Tsilioni I, Theoharides TC. Extracellular vesicles are increased in the serum of children with autism spectrum disorder, contain mitochondrial DNA, and stimulate human microglia to secrete IL-1β. J Neuroinflammation. 2018;15(1):239.
     View this article via: CrossRef PubMed Google Scholar
107. Boilard E, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science. 2010;327(5965):580–583.
     View this article via: CrossRef PubMed Google Scholar
108. Zhang HG, et al. A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death. J Immunol. 2006;176(12):7385–7393.
     View this article via: CrossRef PubMed Google Scholar
109. Sarkar S, et al. Manganese activates NLRP3 inflammasome signaling and propagates exosomal release of ASC in microglial cells. Sci Signal. 2019;12(563):eaat9900.
     View this article via: CrossRef PubMed Google Scholar
110. Li Y, et al. Extracellular MAVS associates with microvesicles that can actively trigger IFNβ production. J Invest Dermatol. 2019;139(5):S9.
     View this article via: CrossRef Google Scholar
111. Vega VL, et al. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol. 2008;180(6):4299–4307.
     View this article via: CrossRef PubMed Google Scholar
112. Jungel A, et al. Microparticles stimulate the synthesis of prostaglandin E(2) via induction of cyclooxygenase 2 and microsomal prostaglandin E synthase 1. Arthritis Rheum. 2007;56(11):3564–3574.
     View this article via: CrossRef PubMed Google Scholar
113. Verma VK, et al. Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. J Hepatol. 2016;64(3):651–660.
     View this article via: CrossRef PubMed Google Scholar
114. Rausch L, et al. Phosphatidylserine-positive extracellular vesicles boost effector CD8⁺ T cell responses during viral infection. Proc Natl Acad Sci U S A. 2023;120(16):e2210047120.
     View this article via: CrossRef PubMed Google Scholar
115. Rhys HI, et al. Neutrophil microvesicles from healthy control and rheumatoid arthritis patients prevent the inflammatory activation of macrophages. EBioMedicine. 2018;29:60–69.
     View this article via: CrossRef PubMed Google Scholar
116. Ostergaard O, et al. Unique protein signature of circulating microparticles in systemic lupus erythematosus. Arthritis Rheum. 2013;65(10):2680–2690.
     View this article via: CrossRef PubMed Google Scholar
117. Yoshida K, et al. Extracellular vesicles of P. gingivalis-infected macrophages induce lung injury. Biochim Biophys Acta Mol Basis Dis. 2021;1867(11):166236.
     View this article via: CrossRef PubMed Google Scholar
118. Marsman G, et al. Extracellular histones, cell-free DNA, or nucleosomes: differences in immunostimulation. Cell Death Dis. 2016;7(12):e2518.
     View this article via: CrossRef PubMed Google Scholar
119. Li Y, et al. Keratinocyte derived extracellular vesicles mediated crosstalk between epidermis and dermis in UVB-induced skin inflammation. Cell Commun Signal. 2024;22(1):461.
     View this article via: CrossRef PubMed Google Scholar
120. Yang J, et al. A new horizon of precision medicine: combination of the microbiome and extracellular vesicles. Exp Mol Med. 2022;54(4):466–482.
     View this article via: CrossRef PubMed Google Scholar
121. Zhu LT, et al. Diverse functional genes harboured in extracellular vesicles from environmental and human microbiota. J Extracell Vesicles. 2022;11(12):e12292.
     View this article via: CrossRef PubMed Google Scholar
122. Tsering T, et al. Extracellular vesicle-associated DNA: ten years since its discovery in human blood. Cell Death Dis. 2024;15(9):668.
     View this article via: CrossRef PubMed Google Scholar
123. Nandakumar R, et al. Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signalling. Nat Microbiol. 2019;4(4):701–713.
     View this article via: CrossRef PubMed Google Scholar
124. Luo Z, et al. CRIg⁺ macrophages prevent gut microbial DNA-containing extracellular vesicle-induced tissue inflammation and insulin resistance. Gastroenterology. 2021;160(3):863–874.
     View this article via: CrossRef PubMed Google Scholar
125. Kwaku GN, et al. Extracellular vesicles from diverse fungal pathogens induce species-specific and endocytosis-dependent immunomodulation [preprint]. https://doi.org/10.1101/2025.01.03.631181 Posted on bioRxiv January 3, 2025.
126. Ye W, et al. Plasma-derived exosomes contribute to inflammation via the TLR9-NF-κB pathway in chronic heart failure patients. Mol Immunol. 2017;87:114–121.
     View this article via: CrossRef PubMed Google Scholar
127. Torralba D, et al. Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts. Nat Commun. 2018;9(1):2658.
     View this article via: CrossRef PubMed Google Scholar
128. Arispe N, et al. Hsc70 and Hsp70 interact with phosphatidylserine on the surface of PC12 cells resulting in a decrease of viability. FASEB J. 2004;18(14):1636–1645.
     View this article via: CrossRef PubMed Google Scholar
129. Komarova EY, et al. Hsp70-containing extracellular vesicles are capable of activating of adaptive immunity in models of mouse melanoma and colon carcinoma. Sci Rep. 2021;11(1):21314.
     View this article via: CrossRef PubMed Google Scholar
130. Barnes BJ, Somerville CC. Modulating cytokine production via select packaging and secretion from extracellular vesicles. Front Immunol. 2020;11:1040.
     View this article via: CrossRef PubMed Google Scholar
131. Liu ML, et al. Cholesterol-induced membrane microvesicles as novel carriers of damage-associated molecular patterns: mechanisms of formation, action, and detoxification. Arterioscler Thromb Vasc Biol. 2012;32(9):2113–2121.
     View this article via: CrossRef PubMed Google Scholar
132. Wolf M, et al. A functional corona around extracellular vesicles enhances angiogenesis, skin regeneration and immunomodulation. J Extracell Vesicles. 2022;11(4):e12207.
     View this article via: CrossRef PubMed Google Scholar
133. Dietz L, et al. Uptake of extracellular vesicles into immune cells is enhanced by the protein corona. J Extracell Vesicles. 2023;12(12):e12399.
     View this article via: CrossRef PubMed Google Scholar
134. Dunn GP, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–998.
     View this article via: CrossRef PubMed Google Scholar
135. Liu S, et al. Reprogramming exosomes to escape from immune surveillance for mitochondrial protection in hepatic ischemia-reperfusion injury. Theranostics. 2024;14(1):116–132.
     View this article via: CrossRef PubMed Google Scholar
136. Ovadya Y, et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun. 2018;9(1):5435.
     View this article via: CrossRef PubMed Google Scholar
137. Russo MV, McGavern DB. Immune surveillance of the CNS following infection and Injury. Trends Immunol. 2015;36(10):637–650.
     View this article via: CrossRef PubMed Google Scholar
138. Ander SE, et al. Innate immune surveillance of the circulation: A review on the removal of circulating virions from the bloodstream. PLoS Pathog. 2022;18(5):e1010474.
     View this article via: CrossRef PubMed Google Scholar
139. Xu R, et al. Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging. Adv Sci (Weinh). 2023;10(36):e2303946.
     View this article via: PubMed Google Scholar
140. Milo T, et al. Autoimmune thyroid diseases as a cost of physiological autoimmune surveillance. Trends Immunol. 2023;44(5):365–371.
     View this article via: CrossRef PubMed Google Scholar
141. Iannello A, et al. Immunosurveillance and immunotherapy of tumors by innate immune cells. Curr Opin Immunol. 2016;38:52–58.
     View this article via: CrossRef PubMed Google Scholar
142. den Hartog G, et al. Immune surveillance for vaccine-preventable diseases. Expert Rev Vaccines. 2020;19(4):327–339.
     View this article via: CrossRef PubMed Google Scholar
143. Stanton SE, et al. Advances and challenges in cancer immunoprevention and immune interception. J Immunother Cancer. 2024;12(3):e007815.
     View this article via: CrossRef PubMed Google Scholar
144. Rojas M, et al. Antigen-specific T cells and autoimmunity. J Autoimmun. 2024;148:103303.
     View this article via: CrossRef PubMed Google Scholar
145. Clarke AE, et al. Risk of malignancy in patients with systemic lupus erythematosus: Systematic review and meta-analysis. Semin Arthritis Rheum. 2021;51(6):1230–1241.
     View this article via: CrossRef PubMed Google Scholar
146. Fletcher K, Johnson DB. Chronic immune-related adverse events arising from immune checkpoint inhibitors: an update. J Immunother Cancer. 2024;12(7):e008591.
     View this article via: CrossRef PubMed Google Scholar
147. Zitvogel L, et al. Beneficial autoimmunity improves cancer prognosis. Nat Rev Clin Oncol. 2021;18(9):591–602.
     View this article via: CrossRef PubMed Google Scholar
148. Mackensen A, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022;28(10):2124–2132.
     View this article via: CrossRef PubMed Google Scholar
149. Mangani D, et al. Learning from the nexus of autoimmunity and cancer. Immunity. 2023;56(2):256–271.
     View this article via: CrossRef PubMed Google Scholar
150. Mackenzie KJ, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017;548(7668):461–465.
     View this article via: CrossRef PubMed Google Scholar
151. Spektor A, et al. Cell biology: when your own chromosomes act like foreign DNA. Curr Biol. 2017;27(22):R1228–R1231.
     View this article via: CrossRef PubMed Google Scholar
152. Teo Hansen Selno A, et al. High mobility group box 1 (HMGB1) induces toll-like receptor 4-mediated production of the immunosuppressive protein galectin-9 in human cancer cells. Front Immunol. 2021;12:675731.
     View this article via: CrossRef PubMed Google Scholar
153. Liu G, et al. High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine. J Immunol. 2008;181(6):4240–4246.
     View this article via: CrossRef PubMed Google Scholar
154. de Mingo Pulido Á, et al. The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake. Immunity. 2021;54(6):1154–1167.
     View this article via: CrossRef PubMed Google Scholar
155. Gorgulho CM, et al. Johnny on the spot-chronic inflammation is driven by HMGB1. Front Immunol. 2019;10:1561.
     View this article via: CrossRef PubMed Google Scholar
156. Zhang HG, Grizzle WE. Exosomes and cancer: a newly described pathway of immune suppression. Clin Cancer Res. 2011;17(5):959–964.
     View this article via: CrossRef PubMed Google Scholar
157. Federici C, et al. Natural-killer-derived extracellular vesicles: immune sensors and interactors. Front Immunol. 2020;11:262.
     View this article via: CrossRef PubMed Google Scholar
158. Lugini L, et al. Immune surveillance properties of human NK cell-derived exosomes. J Immunol. 2012;189(6):2833–2842.
     View this article via: CrossRef PubMed Google Scholar
159. Wen C, et al. Biological roles and potential applications of immune cell-derived extracellular vesicles. J Extracell Vesicles. 2017;6(1):1400370.
     View this article via: CrossRef PubMed Google Scholar
160. Dosil SG, et al. Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses. Elife. 2022;11:e76319.
     View this article via: CrossRef PubMed Google Scholar
161. Lin C, et al. Roles of regulatory T cell-derived extracellular vesicles in human diseases. Int J Mol Sci. 2022;23(19):11206.
     View this article via: CrossRef PubMed Google Scholar
162. Cheng AN, et al. Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles. J Immunother Cancer. 2020;8(2):e001372.
     View this article via: CrossRef PubMed Google Scholar
163. Liang J, Yin H. STAM transports STING oligomers into extracellular vesicles, down-regulating the innate immune response. J Extracell Vesicles. 2023;12(3):e12316.
     View this article via: CrossRef PubMed Google Scholar
164. Jang SC, et al. ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance. Commun Biol. 2021;4(1):497.
     View this article via: CrossRef PubMed Google Scholar
165. Liu ML, et al. Cholesterol enrichment of human monocyte/macrophages induces surface exposure of phosphatidylserine and the release of biologically-active tissue factor-positive microvesicles. Arterioscler Thromb Vasc Biol. 2007;27(2):430–435.
     View this article via: CrossRef PubMed Google Scholar
166. Nagata S, Segawa K. Sensing and clearance of apoptotic cells. Curr Opin Immunol. 2021;68:1–8.
     View this article via: CrossRef PubMed Google Scholar
167. Jaiswal S, et al. Macrophages as mediators of tumor immunosurveillance. Trends Immunol. 2010;31(6):212–219.
     View this article via: CrossRef PubMed Google Scholar
168. Birge RB, et al. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ. 2016;23(6):962–978.
     View this article via: CrossRef PubMed Google Scholar
169. Nagata S, et al. Autoimmunity and the clearance of dead cells. Cell. 2010;140(5):619–630.
     View this article via: CrossRef PubMed Google Scholar
170. Gaipl US, et al. Clearance deficiency and systemic lupus erythematosus (SLE). J Autoimmun. 2007;28(2-3):114–121.
     View this article via: CrossRef PubMed Google Scholar
171. Antwi-Baffour S, et al. Human plasma membrane-derived vesicles inhibit the phagocytosis of apoptotic cells--possible role in SLE. Biochem Biophys Res Commun. 2010;398(2):278–283.
     View this article via: CrossRef PubMed Google Scholar
172. Bijl M, et al. Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement. Ann Rheum Dis. 2006;65(1):57–63.
     View this article via: CrossRef PubMed Google Scholar
173. Logtenberg MEW, et al. The CD47-SIRPα immune checkpoint. Immunity. 2020;52(5):742–752.
     View this article via: CrossRef PubMed Google Scholar
174. Feng M, et al. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19(10):568–586.
     View this article via: CrossRef PubMed Google Scholar
175. Han MH, et al. Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice. J Exp Med. 2012;209(7):1325–1334.
     View this article via: CrossRef PubMed Google Scholar
176. Shi L, et al. CD47 deficiency ameliorates autoimmune nephritis in Fas(lpr) mice by suppressing IgG autoantibody production. J Pathol. 2015;237(3):285–295.
     View this article via: CrossRef PubMed Google Scholar
177. Shimizu A, et al. Exosomal CD47 plays an essential role in immune evasion in ovarian cancer. Mol Cancer Res. 2021;19(9):1583–1595.
     View this article via: CrossRef PubMed Google Scholar
178. Han X, et al. PD-1H (VISTA)-mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus. Sci Transl Med. 2019;11(522):eaax1159.
     View this article via: CrossRef PubMed Google Scholar
179. Chen G, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560(7718):382–386.
     View this article via: CrossRef PubMed Google Scholar
180. Ricklefs FL, et al. Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv. 2018;4(3):eaar2766.
     View this article via: CrossRef PubMed Google Scholar
181. Rao C, et al. Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8⁺ T cell activity and biomarker during the evolution of type 1 diabetes. Diabetologia. 2025;68(2):382–396.
     View this article via: CrossRef PubMed Google Scholar
182. Xu F, et al. Mesenchymal stem cell-derived extracellular vesicles with high PD-L1 expression for autoimmune diseases treatment. Adv Mater. 2022;34(1):e2106265.
     View this article via: CrossRef PubMed Google Scholar
183. Zhou X, et al. The function and clinical application of extracellular vesicles in innate immune regulation. Cell Mol Immunol. 2020;17(4):323–334.
     View this article via: CrossRef PubMed Google Scholar
184. Lundholm M, et al. Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion. PLoS One. 2014;9(9):e108925.
     View this article via: CrossRef PubMed Google Scholar
185. Vulpis E, et al. Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle-associated MICA: Dual role in cancer immunosurveillance. J Extracell Vesicles. 2022;11(1):e12176.
     View this article via: CrossRef PubMed Google Scholar
186. Ricklin D, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–797.
     View this article via: CrossRef PubMed Google Scholar
187. MacDonald KM, et al. Alerting the immune system to DNA damage: micronuclei as mediators. Essays Biochem. 2020;64(5):753–764.
     View this article via: CrossRef PubMed Google Scholar
188. Fan J, et al. Macrophages are disarmed by CD 47(+) microvesicles for their impaired phagocytotic capability in atherosclerosis. Circ Res. 2018;(12):123.
189. Welsh JA, et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J Extracell Vesicles. 2024;13(2):e12404.
     View this article via: CrossRef PubMed Google Scholar
190. Li G, et al. Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases. J Extracell Vesicles. 2023;12(2):e12305.
     View this article via: CrossRef PubMed Google Scholar
191. Jin Y, et al. Extracellular vesicle as a next-generation drug delivery platform for rheumatoid arthritis therapy. J Control Release. 2025;381:113610.
     View this article via: CrossRef PubMed Google Scholar
192. Xu Y, et al. Macrophages transfer antigens to dendritic cells by releasing exosomes containing dead-cell-associated antigens partially through a ceramide-dependent pathway to enhance CD4(+) T-cell responses. Immunology. 2016;149(2):157–171.
     View this article via: CrossRef PubMed Google Scholar