Exosomes consist of a phospholipid bilayer enclosing a diverse repertoire of biomolecules, including proteins, lipids, nucleic acids and metabolites (22). Their lipid composition, rich in sphingolipids and cholesterol, ensures structural stability and functional versatility (23). Proteomic analysis identifies a conserved protein signature, including tetraspanins (CD9, CD63, CD81), heat shock proteins, major histocompatibility complex (MHC) molecules (MHC-I/II), transmembrane proteins (CD13, LAM1/2, PGRL) and various enzymes (23, 24). These proteins repertoire serves as a marker of the exosomes cellular origin and governs their interactions with recipient cells. These proteins not only reflect the cellular origin of exosomes but also mediate their uptake and biological effects on recipient cells.

Exosomes are particularly enriched in RNA species, particularly miRNAs. Other cargoes include small nuclear RNAs (snRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), lncRNAs, circRNAs and fragmented transcripts (25, 26). Importantly, exosomal mRNAs and miRNAs remain functional upon transfer, regulating gene expression in recipient cells and serving as a “molecular language” for intercellular communication (25, 27). Therefore, systematic profiling of exosomal cargo is pivotal for biomarker discovery and therapeutic development.

Exosome formation is a highly orchestrated process that involves sequential endosomal maturation and membrane remodeling. Plasma membrane invagination generates early sorting endosomes (ESEs), which can also receive input from the trans-Golgi network (TGN), endoplasmic reticulum (ER) and mitochondria (28–30). ESEs mature into late sorting endosomes (LSEs) and ultimately multivesicular bodies (MVBs), formed by inward budding of the endosomal membrane. Most MVBs fuse with lysosomes for degradation, whereas a subset regulated by Rab27a/b and other exocytic machinery fuse with the plasma membrane to release intraluminal vesicles (ILVs) as exosomes (28, 31–33).

The molecular machinery underlying MVB and ILV formation primarily relies on the endosomal sorting complex required for transport (ESCRT) pathway (34). The canonical pathway involves four ESCRT complexes (0–III), the ATPase VPS4, and multiple accessory proteins, which act in a coordinated manner to cluster cargo and drive ILV budding. Non-canonical ESCRT-dependent mechanisms bypass upstream complexes by directly recruiting ESCRT-III and VPS4 to endosomal membranes (35, 36). In addition, ESCRT-independent mechanisms mediated by the melanosomal protein Pmel17, tetraspanin CD63, proteolipid protein and sphingomyelinase (SMase or SMPD2), contribute to ILV generation (33, 37, 38). Together, these complementary pathways constitute the molecular basis of exosome biogenesis.

Exosomes function as versatile messengers in both physiological and pathological contexts (39, 40). By transferring bioactive molecules reflective of their parental cells, exosomes participate in immune regulation, angiogenesis, tissue repair, proliferation, and inflammatory responses (41). Their functions are mediated through three principal mechanisms. Initially, ligand-receptor cognate recognition on the exosomal membrane facilitates intercellular communication via signal transduction. Subsequently, cargo deployment through membrane fusion with target cells enables macromolecular trafficking of genetic material and signature biomolecules. Finally, the release of proteins and miRNAs modulates target cell biology by engaging surface receptors, triggering intracellular signal transduction cascades that ultimately altering cellular function (42, 43).

Collectively, exosomes represent highly specialized communication modules defined by distinctive biogenesis pathways and molecular signatures. Their stability, accessibility in body fluids and cargo specificity, underscore their potential as biomarkers for early diagnosis, prognostic monitoring, and therapeutic targeting in human disease (Figure 1).

Exosomes derived from immune and non-immune cells act as intercellular messengers, delivering ncRNAs that modulate immune regulation. Their immunomodulatory effects span immune cell crosstalk, T helper subset balance and macrophage polarization.

Oxidative stress, characterized by excess reactive oxygen species (ROS), disrupts redox balance and promotes tissue damage in autoimmune diseases. Exosomal ncRNAs mitigate or exacerbate these processes. HucMSCs-ex carrying miR-140-3p suppress TNF-α and IL-1β production, reduce malondialdehyde, and enhance SOD activity in RA (68). Dysregulated exosomal miRNAs in RA, such as miRNA-103a-3p, miRNA-10a-5p, miRNA-204-3p, miRNA-330-3p and miRNA-19b, are linked to aberrant histone deacetylation and oxidative stress (69). In vitiligo, ROS-induced melanocyte-derived exosomes disrupt immune tolerance, whereas 3D-cultured human mesenchymal stem cells -derived exosomes (3D-hucMSCs-ex) enriched in miR-132-3p and miR-125b-5p restore Treg function and attenuate melanocyte injury (70, 71). Conversely, keratinocyte exosomal miR-31-3p exacerbates melanocyte destruction and CD8⁺ T cell activation under oxidative stress (72).

Furthermore, disruption of intestinal immune homeostasis leads to aberrant inflammatory responses and the accumulation of ROS. Consequently, targeted ROS clearance is a critical therapeutic approach. In IBD, oxidative stress impairs barrier integrity. Peroxiredoxin 3 (Prdx3) deficiency enhances colitis severity via exosomal miR-1260b–mediated intestinal barrier disruption and p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) activation (73). Together, these findings highlight oxidative stress as a key pathogenic mechanism modulated by exosomal ncRNAs across autoimmune contexts.

Autophagy constitutes an evolutionarily conserved intracellular degradation pathway that is essential for maintaining cellular homeostasis by degrading and recycling damaged organelles, misfolded proteins, and other cytoplasmic components. Under normal conditions, autophagy serves as an adaptive mechanism that promotes cell survival by mitigating cellular stress and maintaining energy homeostasis. However, excessive or dysregulated autophagy can induce cell death, characterized by distinct morphological hallmarks that may contribute to disease pathogenesis (74). Exosomal ncRNAs modulate this process, linking autophagy to autoimmune disease pathogenesis. Exosomal miR-20b-3p alleviates diabetic peripheral neuropathy by targeting STAT3 and restoring Schwann cell autophagy (75). Similarly, adipose MSC exosomal miR-486 inhibits smad1, suppresses mTOR activation, and enhances podocyte autophagy in diabetic nephropathy (DN) (76). In Crohn’s disease, intestinal epithelial cells derived exosomes (IECs-ex) deliver miRNAs that restore ATG5/ATG16L1 expression, counteracting bacterial inhibition of autophagy (77). Circulating exosomal miR-376a-3p and miR-20a-5p also regulate systemic autophagy pathways in Crohn’s patients (78). Furthermore, In SLE, altered plasma exosomal miR-20b-5p and miR-181a-2-3p promote apoptosis and autophagy in renal cells, aggravating lupus nephritis (79), while exosomal miR-20a modulates the mTOR pathway to attenuate renal injury (80). These studies position exosomal ncRNAs as dual modulators of autophagy, either protective or pathogenic depending on disease context.

Exosomal ncRNAs critically modulate cell cycle, specifically proliferation and division in autoimmune disorders, mechanistically driving pathological progression via dysregulation of cell cycle. In RA, plasma exosomal circ_0003914 promotes fibroblast-like synoviocyte (FLSs) proliferation and cytokine secretion via NF-κB/p65 activation (81), while TNF-α–stimulated FLSs.

-ex enhance angiogenesis in endothelial cells through the miR-200a-3p/KLF6/VEGFA axis (82). By contrast, MSCs-ex deliver miR-451a or circFBXW7 to suppress FLSs proliferation and inflammation, alleviating joint damage in arthritis models. MiR-451a-loaded hucMSCs-ex attenuated RA progression by targeting activating transcription factor 2 (ATF2), thereby suppressing synovial fibroblast proliferation, migration, and invasion, while ameliorating joint inflammation and radiographic abnormalities in CIA rats (83). Exosomal circFBXW7 suppressed proliferation, migration and inflammatory response of RA-FLSs and release the activation of HDAC4, thereby reducing joint damage of RA rats (84).

In addition, it was demonstrated that overexpression of exosomal miR-142-3p/−5p and miR-155 derived from T cells was sufficient to induce β-cell death, suggesting their contribution to the progression of T1DM (85). Whereas Treg-derived exosomes carrying miR-195a-3p support epithelial proliferation and reduce inflammation in colitis models (86). Thus, exosomal ncRNAs exert dual, context-dependent effects on cell cycle regulation, amplifying pathology in some settings while restraining it in others (Table 1) (Figure 2).

In summary, exosomal ncRNAs do not function in isolation but orchestrate a complex network to regulate autoimmune pathogenesis. Functionally, they orchestrate immune homeostasis through mediating immune cell crosstalk, balancing Th17/Treg subsets, and directing macrophage polarization (M1/M2 shift). However, their impact exhibits a clear duality primarily dictated by their cellular origin, target molecules, and the disease microenvironment (87, 88). Pathogenic exosomal ncRNAs, predominantly derived from activated immune cells or damaged parenchymal cells, drive autoimmune progression by disrupting immune tolerance, promoting pro-inflammatory phenotypes and inducing tissue damage. In contrast, protective exosomal ncRNAs, mostly derived from MSCs, alleviate autoimmune pathology by restoring immune homeostasis, suppressing oxidative stress and regulating autophagy.

Mechanistically, the four categories discussed (immune response, oxidative stress, autophagy and cell cycle regulation) are deeply interconnected. Exosomal ncRNAs regulate redox balance by altering ROS production and scavenging, modulate autophagic flux to maintain cellular homeostasis or induce cell death, and disrupt cell proliferation/differentiation cycles in disease-relevant cells. Crucially, these pathways often form a positive feedback loop: exosomal ncRNA-induced pro-inflammatory activation boosts ROS production, while excessive ROS further amplifies immune cell infiltration and cytokine secretion, exacerbating autoimmune pathology (72, 73). Furthermore, these mechanisms often converge on shared signaling hubs. Notably, the NF-κB signaling pathway serves as a common downstream mediator across multiple mechanisms, integrating signals from exosomal ncRNA-regulated immune response, oxidative stress and autophagy. For instance, exosomal miR-122-5p promotes M1 macrophage polarization via NF-κB activation in SLE, while circ_0003914 activates NF-κB/p65 to drive FLSs proliferation in RA (64, 81). This pathway convergence highlights potential therapeutic targets for simultaneous intervention in multiple pathogenic processes.

RA is a chronic autoimmune disease driven by persistent synovitis, bone erosion, and cartilage destruction, leading to irreversible joint deformities and disability (89). Although the pathogenesis of RA is not fully understood, current evidence indicates that genetic variants, dysregulated protein translation and post-translational modifications, and various environmental factors contribute to the onset and progression of the disease (90). Exosomal ncRNAs also emerge as key mediators in rheumatoid arthritis pathogenesis, actively contributing to inflammatory cascades under defined pathological states.

FLSs serve as pivotal orchestrators in rheumatoid arthritis pathogenesis. Their dysregulated activation and proliferation drive the secretion of inflammatory mediators (e.g., CXCL8, IL-6, IL-15), concomitant upregulation of adhesion molecules, and excessive production of extracellular matrix components such as fibronectin. These pathological alterations collectively potentiate leukocyte activation and recruitment into synovial microenvironments (91, 92). Exosomal circRNA hsa_circ_0003914 from RA plasma promotes aberrant FLSs proliferation and cytokine release through NF-κB/p65 signaling (81), while FLSs-derived exosomal miR-424, induced by synovial hypoxia, inhibits Treg differentiation and enhances Th17 expansion, tipping the Th17/Treg balance toward inflammation (93). Moreover, exosomal cargo also fuels synovial angiogenesis, with vascular endothelial growth factor (VEGF) and miR-200a-3p supporting hyperplasia and immune cell infiltration (82).

Beyond synovial inflammation, exosomes impair bone and cartilage homeostasis. The inhibition of osteoclast differentiation, proliferation, and mineralization constitutes a demonstrated mechanism that exacerbates disease progression. RA-FLSs exosomal miR-486-5p suppresses osteoblast proliferation and mineralization by targeting BMP/Smad–Tob1 signaling (94). Similarly, FLSs-derived exosomal lncRNA TRAFD1-4:1 sponges miR-27a-3p to upregulate CXCL1, driving extracellular matrix degradation and chondrocyte dysfunction.

Emerging evidence demonstrates that exosomal ncRNAs also contribute to RA pathogenesis by modulating immune cell polarization. Circ-CBLB–enriched exosomes activate TLR3/TRAF3 signaling to promote M1 polarization, while m⁶A modifications enhance circ-CBLB expression, underscoring the epigenetic regulation of inflammatory cascades (95).

SLE is characterized by autoreactive lymphocyte activation, autoantibody production, and immune complex deposition, driving multi-organ injury (96). Among the complications of SLE, LN remains the leading cause of morbidity and mortality (97). During the incipient phase of SLE, exosomes regulate pathological immune activation through coordinated delivery of self-antigens and immunostimulatory molecules, thereby potentiating maladaptive recognition and targeted destruction of host tissues by autoreactive immune components. Exosomal miR-451a, enriched in CD4⁺ T cells and B cells, augments autoreactive responses (98).

A pivotal feature of SLE pathogenesis involves dysregulated B-cell activation, which drives excessive autoantibody production and inflammatory responses, ultimately culminating in tissue damage. Activated basophil-derived exosomes deliver lncRNA ENST00000537616, which sponges miR-330-5p to activate KRAS signaling, thereby potentiating B cell activation; silencing this lncRNA attenuates hyperactivation and improves renal pathology in murine lupus (52). Moreover, Senescence of MSCs plays a critical pathogenic mechanism contributing to the progression of SLE. Exosomal miR-146a mitigates MSCs senescence by targeting TRAF6/NF-κB, restraining disease progression (99).

Exosomal ncRNAs are also key drivers of renal pathology. Studies demonstrate that miR-20b-5p in plasma exosomes from patients with SLE mediates the promotion of apoptosis and autophagy in renal epithelial cells, thereby contributing to renal injury and the progression of LN (79). Plasma-derived exosomes from patients with SLE were found to accelerate disease progression and renal macrophage polarization in MRL/lpr mice. MiR-122-5p, upregulated in patient-derived exosomes, correlates with disease activity and dsDNA titers, promoting M1 macrophage polarization via FOXO3/NF-κB signaling (64). Furthermore, urinary exosomal miR-21 and let-7a activate NF-κB signaling in mesangial cells, amplifying inflammatory and fibrotic responses in LN (100).

T1DM results from T cell–mediated β-cell destruction, often presenting with diabetic ketoacidosis in children and adolescents. Exosomal ncRNAs modulate both beta-cell vulnerability and immune activation. For example, T cell–derived exosomes carrying miR-142-3p, miR-142-5p, and miR-155 induce β-cell apoptosis and upregulate chemokines (Ccl2, Ccl7, Cxcl10), facilitating immune recruitment (85). In addition, the pathogenesis of T1DM is characterized by insulin deficiency or dysfunction, leading to impaired glucose uptake and subsequent hyperglycemia. Adipocyte-derived exosomal miR-138-5p suppresses insulin secretion via SOX4/Wnt/β-catenin signaling (101).

T cells as pathogenic effector cells in TIDM are also well established. A fundamental pathological process in T1DM is characterized by the infiltration of activated T lymphocytes into the pancreas, inducing insulitis and the consequent loss of β-cells. A recent study demonstrates that MSCs-derived exosomal miR-25 reduces pancreatic infiltration of activated T cells by downregulating CXCR3, thereby alleviating insulitis (102).

IBD, comprising Crohn’s disease and ulcerative colitis, arises from the interplay of genetic susceptibility, microbial dysbiosis, and immune dysregulation (103). Exosomes serve as critical vehicles for ncRNA delivery, contributing significantly to the multifactorial pathogenesis of IBD. Exosomal ncRNAs influence disease through macrophage activation, epithelial barrier integrity, and host–microbiota interactions.

Macrophages are central to intestinal immune homeostasis, and their dysregulation fuels chronic inflammation. NLRP3 inflammasome activation-induced macrophage pyroptosis is implicated in the aberrant immune response underlying IBD pathogenesis. HucMSCs-ex mitigate colitis by suppressing caspase-11/4–mediated pyroptosis in macrophages. Specifically, exosomal miR-203a-3p.2 inhibits caspase-4 activation, while miR-378a-5p dampens NLRP3 inflammasome activity, reducing IL-1β/IL-18 release and limiting pyroptotic cell death (104, 105).

IECs, forming the intestinal epithelium, are essential for the physical and biochemical barrier that segregates host tissues from commensal bacteria to maintain intestinal homeostasis. Disruption of this barrier function, particularly through an imbalance between cellular antioxidant defenses and oxidative stress, is a key driver in the pathogenesis of IBD. As an intracellular antioxidant enzyme specifically localized within mitochondria, Prdx3 confers protection against oxidative stress through the scavenging of mitochondrial ROS. Notably, Loss of the mitochondrial antioxidant enzyme Prdx3 exacerbates DSS-induced colitis through exosomal miR-1260b, which disrupts barrier integrity and enhances proinflammatory signaling (73). In contrast, hucMSCs-ex enriched in miR-129-5p suppress ACSL4-dependent lipid peroxidation, restoring epithelial barrier function and attenuating experimental colitis (106).

Additionally, exosomal miRNAs derived from gut microbiota further shape host immunity. Enterotoxigenic Bacteroides fragilis (ETBF) reduces serum exosomal miR-149-3p via METTL14-mediated m⁶A methylation. The resulting depletion of miR-149-3p promotes Th17 differentiation and accelerates IBD progression, underscoring a direct microbiota–exosome–immune axis (107).

SS is defined by lymphocytic infiltration of salivary and lacrimal glands, leading to progressive glandular dysfunction with xerostomia and keratoconjunctivitis sicca (108). Exosomal ncRNAs critically mediate immune–epithelial crosstalk and aberrant B cell activation in disease pathogenesis.

Activated T cell–derived exosomes in SS transfer miR-142-3p to salivary epithelial cells, suppressing sarco (endo) plasmic reticulum Ca²⁺ ATPase 2b (SERCA2b), ryanodine receptor 2 (RyR2), and adenylate cyclase 9 (AC9). This disrupts Ca²⁺ signaling and cAMP production, impairing protein synthesis and glandular secretion (109). Similarly, EBV-infected B cells deliver exosomal viral miRNA BART13-3p to epithelial cells, where it represses stromal interaction molecule 1 (STIM1) and aquaporin 5 (AQP5). The resulting defects in store-operated Ca²⁺ entry and nuclear factor of activated T cells (NFAT) signaling culminate in reduced saliva secretion (110).

Aberrant B cell activation is another hallmark of SS. Xing et al. investigate the effects of Labial gland mesenchymal stem cells derived exosomes (LGMSCs-ex) on a mouse model of pSS and elucidate their regulatory mechanisms on B cell subsets. Their findings demonstrate that in vivo administration of LGMSC-ex to spontaneous pSS mice ameliorates salivary gland inflammatory infiltration and restores saliva secretion. In vitro, co-culture of LGMSCs-ex with peripheral blood mononuclear cells (PBMCs) from pSS patients significantly reduces the proportion of CD19⁺CD20^-CD27⁺CD38⁺ plasma cells. Furthermore, mechanistic studies reveal that miR-125b derived from LGMSCs-ex directly targets PRDM1 in pSS plasma cells. Thus, the miR-125b/PRDM1 axis, by targeting PRDM1 and suppressing plasma cells, represents a promising therapeutic target for pSS (111).

Exosomal ncRNAs have emerged as promising candidates for early and accurate diagnosis of autoimmune diseases. Their stability in circulation, non-invasive accessibility, and disease-specific expression patterns confer unique advantages over conventional laboratory assays. Across multiple ADs, distinct ncRNA signatures encompassing miRNAs, lncRNAs, and circRNAs have been identified as biomarkers that not only differentiate patients from healthy controls but also correlate with disease activity and therapeutic response. Below, we summarize their diagnostic potential across representative autoimmune disorders.

Accumulating evidence suggests that exosomal ncRNAs not only act as biomarkers but also play therapeutic roles in autoimmune diseases. By delivering functional ncRNAs, exosomes can modulate immune responses, inhibit inflammatory signaling, restore immune tolerance, and promote tissue repair. This section summarizes current findings on their therapeutic potential in representative ADs.