Exosomal non-coding RNAs: gatekeepers of inflammation in autoimmune disease

Abstract

Autoimmune diseases (AIDs) are marked by systemic inflammation and immune dysregulation, yet current therapies often fail to target their underlying causes. Emerging evidence positions exosomal non-coding RNAs (ncRNAs)—including miRNAs, lncRNAs, and circRNAs—as key regulators of inflammatory pathways, providing critical insights into AID pathogenesis. This review synthesizes recent advances in how these ncRNAs orchestrate immune cell communication, modulate inflammatory mediators, and drive microglial activation in neuroinflammatory AIDs. It evaluates their dual role as disease amplifiers (e.g., miR-155 in lupus, miR-326 in rheumatoid arthritis) and therapeutic targets, emphasizing their potential to reprogram immune responses or deliver anti-inflammatory agents. In this review, we first provide a glimpse into the pathogenesis of autoimmune diseases and delve into the structure and function of exosomes, emphasizing their role in cell-cell communication. We then discuss the regulatory roles of exosomal ncRNAs in immune modulation, detailing their types, functions, and mechanisms of action. Finally, we examine the implications of exosomes and exosomal ncRNAs in the context of autoimmune diseases, with a particular focus on microglial activation and its contribution to neuroinflammation.

Introduction

Autoimmune diseases (AIDs) represent a spectrum of disorders characterized by the immune system’s failure to distinguish self from non-self, leading to chronic inflammation and tissue damage [1, 2]. Central to AID pathogenesis is the dysregulation of immune tolerance, where autoreactive T and B lymphocytes are erroneously activated, perpetuating cycles of inflammation [1, 2]. Pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β play pivotal roles in amplifying these responses, often through inflammasome-mediated pathways like NLRP3, which promote caspase-1 activation and subsequent release of IL-1β and IL-18 [3]. This cascade drives immune cell infiltration and autoantibody production, contributing to disease manifestations such as synovial inflammation in rheumatoid arthritis, immune complex deposition in systemic lupus erythematosus, and mucosal barrier disruption in inflammatory bowel disease [4,5,6,7].

Emerging evidence highlights the importance of exosomes—nanoscale extracellular vesicles secreted by various cell types—in regulating immune responses and mediating intercellular communication [8, 9]. Exosomes carry diverse molecular cargoes, including proteins, lipids, non-coding RNAs (ncRNAs) such as microRNAs (miRNA), long-non coding RNAs, and circularRNAs as well as cytokines, enabling them to modulate recipient cell behavior [8,9,10]. For instance, exosomes derived from mesenchymal stem cells or regulatory T cells exhibit immunomodulatory effects, suppressing pro-inflammatory cytokine secretion and enhancing regulatory T-cell activity [11]. Conversely, exosomes released by activated macrophages may propagate inflammation, underscoring their dual role in AID pathogenesis [12]. Therefore, understanding the intricate relationships between inflammation, immune dysregulation, and exosomal communication provides novel insights into AID pathobiology and opens avenues for innovative treatments to restore immune homeostasis [13, 14]. This review examines the critical role of exosomal ncRNAs in AIDs, focusing on their impact on immune dysregulation, inflammation, and neuroinflammation. It evaluates their dual role as both drivers of disease pathogenesis and potential therapeutic targets, while highlighting the promise of exosome-based strategies to restore immune balance and advance precision medicine through biomarker discovery, engineered therapeutics, and targeted drug delivery. By linking exosome biology with ncRNA mechanisms, the review provides insights into innovative interventions targeting the exosomal ncRNA-inflammation axis to improve patient outcomes.

The review was compiled by searching PubMed, and Google Scholar using keywords such as ‘exosomes,’ ‘non-coding RNAs,’ ‘autoimmune diseases,’ and ‘inflammation.’ Studies were selected based on their relevance to exosomal ncRNAs in AID pathogenesis, immune regulation, and therapeutic potential, prioritizing recent publications (2005–2025) and seminal works.

Pathogenesis of autoimmune diseases

Mechanisms of autoimmunity: self vs. non-self recognition

AIDs are characterized by the immune system’s erroneous identification and attack on the body’s own tissues, perceived as foreign. Fundamental mechanisms underlying autoimmunity involve complex interactions among genetic, environmental, and immunological factors that lead to dysregulated immune responses [15, 16].

At the core of autoimmune pathology is the failure of central and peripheral tolerance mechanisms, which normally differentiate self from non-self [17]. Central tolerance occurs in the thymus during T cell development, where thymocytes expressing high-affinity receptors for self-antigens are eliminated through negative selection. However, this process is not infallible, and autoreactive T cells can escape into peripheral tissues, where they may contribute to autoimmunity [18, 19]. Peripheral tolerance mechanisms, including anergy, clonal deletion, and the activity of regulatory T cells (Tregs), are essential for suppressing autoreactive lymphocytes that evade central tolerance. A breakdown of these mechanisms can activate and expand autoreactive T cell populations [20]. For instance, recent studies have shown that defective Treg function in systemic lupus erythematosus (SLE) leads to increased effector T cell activation, perpetuating autoimmunity [21].

Additionally, the concept of molecular mimicry, wherein foreign antigens share structural similarities with self-antigens, can precipitate autoimmunity [22]. A notable example is rheumatic fever, where cross-reactivity occurs between streptococcal M protein and cardiac myosin, leading to autoimmune damage in the heart after bacterial infection (Fig. 1) [23].

Fig. 1

The roles of exosomal non-coding RNAs (ncRNAs) in human autoimmune diseases. This figure illustrates the pivotal roles of exosomal ncRNAs in various human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Alzheimer’s disease, and parkinson. Exosomal ncRNAs, such as microRNAs and long non-coding RNAs, are involved in regulating inflammatory responses and immune cell activation, contributing to the pathogenesis and progression of these diseases. Notably, altered profiles of exosomal ncRNAs in patients highlight their potential as non-invasive biomarkers for disease diagnosis, monitoring progression, and assessing treatment responses

Chronic inflammation and immune dysregulation

Chronic inflammation drives AID by disrupting immune balance, impairing self-recognition, and causing tissue damage. This persistent inflammation intensifies autoimmune reactions, accelerates disease progression, and perpetuates a destructive cycle that worsens tissue destruction and sustains autoimmunity. Initially, an inflammatory response may be beneficial, aiding in pathogen clearance; however, in AIDs, this response becomes pathological. Chronic inflammation is marked by persistent immune cell recruitment, including T cells, B cells, macrophages, and dendritic cells, which release pro-inflammatory cytokines and chemokines, further amplifying the immune response [22, 24, 25].

Key cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β), are pivotal in driving inflammation across various AIDs [26, 27]. In rheumatoid arthritis, TNF-α has been implicated in joint tissue destruction by promoting synovial inflammation and osteoclast activation [28]. In SLE, elevated levels of IL-6 contribute to B cell activation and autoantibody production, exacerbating tissue damage [29]. A recent clinical study found that blocking IL-6 receptor (IL-6R) improved disease activity in patients with chronic inflammatory diseases, affirming its role as a therapeutic target [30, 31].

This persistent inflammatory milieu mediates tissue injury and poses a therapeutic target, as evidenced by the efficacy of anti-TNF therapies in both RA and SLE.

Environmental and genetic triggers of autoimmunity

The complexities of AID pathogenesis are underscored by the involvement of various inflammatory mediators and signaling pathways. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway plays a central role in activating immune cells and regulating pro-inflammatory cytokines [32, 33]. Aberrant NF-κB signaling has been associated with several AIDs, including multiple sclerosis (MS) and RA, highlighting its potential as a therapeutic target. Recent studies have indicated that inhibiting NF-κB can reduce the production of inflammatory cytokines, paving the path for novel therapeutic interventions [34].

Inflammasomes, multi-protein complexes activating inflammatory caspases (e.g., caspase-1), are crucial for the maturation and secretion of pro-inflammatory cytokines such as IL-1β. Dysregulated inflammasome activity has been implicated in the pathogenesis of diseases, including systemic sclerosis and type 1 diabetes [35, 36]. The NLRP3 inflammasome has been shown to play a significant role in type 1 diabetes by contributing to pancreatic β-cell apoptosis through IL-1β secretion, underscoring inflammasome activation as a pivotal event in autoimmunity [1, 37, 38].

Furthermore, the interplay between inflammatory mediators and environmental factors, such as infections, exposure to toxins, and dietary influences, can significantly affect the onset and progression of AIDs [39]. For instance, alterations in gut microbiota have been shown to influence immune responses, correlating with the development of autoimmune pathology [40]. Recent findings suggest that certain bacterial strains (e.g., Lactobacillus spp, Bifidobacterium spp, Faecalibacterium prausnitzii, etc.) can enhance Treg function, proffering a potential preventive strategy against AIDs [41,42,43].

Exosomes: biogenesis, structure, and function

Overview of exosome biogenesis and secretion

Exosomes are nanoscale extracellular vesicles that play a pivotal role in intercellular communication and biomolecular transport within the extracellular environment [44, 45]. They are defined as small, membrane-bound vesicles ranging from 30 to 150 nanometers in diameter and are released by various cell types into the extracellular space [46]. Exosomes constitute a subtype of extracellular vesicles, distinguishable from larger microvesicles (ranging from 150 to 1,000 nanometers) and apoptotic bodies (larger vesicles formed during programmed cell death). Their biogenic distinction primarily arises from their mode of formation and release [47].

Exosomes are composed of a lipid bilayer membrane encapsulating a diverse array of biomolecules, including proteins, lipids, RNA species, and metabolites [48]. The lipid composition of exosomes often features a predominance of sphingolipids and cholesterol, contributing to their stability and functionality. Proteomic analyses reveal that exosomes carry a unique cargo of proteins such as tetraspanins (e.g., CD63, CD81), heat shock proteins, major histocompatibility complex (MHC) molecules, and various enzymes that denote their cellular origin and function in interactions with recipient cells [49, 50]. As previously discussed, the molecular cargoes of exosomes play a critical role in facilitating intercellular communication (see “Introduction”). These cargoes enable the transfer of genetic information and modulate gene expression profiles in recipient cells, as illustrated in Fig. 2.

Fig. 2

This figure illustrates the biogenesis of exosomal microRNAs (miRNAs) and their trafficking pathways. The process begins with the transcription of primary miRNA (pri-miRNA) in the nucleus, where it is processed by different enzymes (including Drosha and Dicer) to form mature miRNAs. Once formed, these miRNAs are incorporated into the cytoplasmic RNA-induced silencing complex (RISC). Exosomes are generated from multivesicular bodies (MVBs) within the endosomal pathway, where miRNAs can be selectively packaged. The exosomes then bud off and are released into the extracellular space, facilitating intercellular communication. These exosomal miRNAs can influence recipient cells by regulating gene expression, thus playing critical roles in various biological processes and disease mechanisms

Exosome biogenesis begins with inward budding of the endosomal membrane, generating multivesicular bodies (MVBs) [51]. Within these MVBs, intraluminal vesicles are formed and subsequently released into the extracellular space upon fusion of MVBs with the plasma membrane [52]. This process involves numerous cellular mechanisms regulated by proteins like the endosomal sorting complex required for transport (ESCRT) machinery, sphingolipid metabolism, and tetraspanin proteins [53].

The ESCRT machinery, including ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III complexes, coordinates sorting of ubiquitinated proteins and lipid-rich regions into intraluminal vesicles, with proteins such as Alix and Tsg101 critical for the membrane remodeling necessary for the budding process. Specific lipids, including ceramide and phosphatidylserine, are implicated in membrane dynamics supporting exosome formation [54].

Exosomes can also be released in response to various stimuli, including cellular stress and cytokine signaling. This modulation can result in alterations in exosomal molecular composition, emphasizing the dynamic nature of exosomal secretion [55].

Exosomes as key regulators of intercellular communication

Exosomes facilitate intercellular communication through bioactive molecule transfer, enabling a myriad of biological effects in recipient cells. They can influence physiological processes such as immune modulation, tissue repair, and neuronal communication [56,57,58].

A key role of exosomes in immune modulation lies in their capacity to present antigens and facilitate immune responses [59]. Dendritic cells, for example, release exosomes containing MHC molecules and co-stimulatory signals, activating T cells and eliciting adaptive immune responses [60]. Furthermore, evidence suggests that tumor-derived exosomes can reprogram recipient immune cells to foster an immunosuppressive environment conducive to tumor growth and metastasis. For example, exosomal PD-L1 (programmed death-ligand 1) can inhibit T-cell activation and promote tumor progression [61, 62].

Exosomes also contribute to tissue repair processes. In myocardial infarction, cardiac stem cell-derived exosomes enhance reparative mechanisms by transferring mRNAs and miRNAs that promote angiogenesis and cardiomyocyte survival [52]. For instance, stem cell-derived exosomal miRNAs, such as miR-19a, miR-21, and others, show cardioprotective effects by improving cardiomyocyte survival and reducing fibrosis [63].

In the nervous system, exosomes facilitate communication through the transfer of neurotrophic factors and RNA species involved in synaptic transmission and plasticity. For instance, pathogenic proteins like amyloid-beta and tau may spread through exosomes in neurodegenerative diseases, suggesting a mechanism for propagating neurodegeneration within neuron networks [64, 65].

In summary, exosomes are integral mediators of intercellular communication characterized by distinct biogenic pathways and cargo composition [66]. Their abilities to facilitate favorable biological effects position them as significant players in various physiological and pathological processes, offering insights into potential therapeutic targets and biomarkers across disease landscapes [67].

Regulatory roles of exosomal non-coding RNAs in immune modulation

Types and functions of non-coding RNAs in exosomes

The intricate landscape of immunological regulation has expanded with the recognition that non-coding RNAs (ncRNAs), particularly those encapsulated within exosomes, play critical roles in modulating immune responses and influencing various pathological processes [68, 69]. Exosomes comprise diverse ncRNA types, broadly classified into microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) [70].

MiRNAs, consisting of approximately 21–23 nucleotides, act as post-transcriptional regulators of gene expression. Numerous studies have demonstrated that exosomal miRNAs, such as miR-155 [71, 72], involved in T cell differentiation and macrophage function regulation, modulate immune responses by binding target messenger RNAs (mRNAs), resulting in mRNA degradation or translation inhibition [64].

LncRNAs, exceeding 200 nucleotides in length, emerge as critical regulators of gene expression through mechanisms such as chromatin remodeling and transcriptional interference. Exosomal lncRNAs, like lnc-IL7R, influence T helper cell differentiation and cytokine production during immune responses. Recent findings suggest that exosomal lncRNAs can also modulate gut microbiota interactions, thus influencing systemic inflammation and autoimmunity [73, 74].

CircRNAs are characterized by their covalently closed-loop structure generated from pre-mRNA back-splicing, making them resistant to exonuclease degradation. Exosomal circRNAs can act as competitive endogenous RNAs (ceRNAs), modulating miRNA availability for target mRNAs. For example, circRNA CDR1as effectively absorbs miR-7, consequently influencing immune-related gene expression in recipient cells [75, 76].

Exosomal NcRNAs in immune cell crosstalk

Exosomal ncRNAs influence immune responses through direct interactions with immune cell types, modulation of signaling pathways, and regulation of gene expression in recipient cells. For instance, exosomes derived from activated T cells are internalized via endocytosis by dendritic cells, releasing miR-146a to target IRAK1 and TRAF6, impairing antigen presentation and reducing T cell activation, thereby fostering an anti-inflammatory environment [77, 78]. MiR-146a is taken up by dendritic cells via endocytosis and targets IRAK1/TRAF6, which reduces NF-κB signaling, mitigating neuroinflammation in conditions such as Alzheimer’s disease [79].

Exosomal ncRNAs also regulate cytokine synthesis and release. For instance, exosomal miR-29a directly targets specific mRNAs involved in cytokine synthesis, modulating TNF-α and IL-6 production in macrophages, delineating a pathway for exosomes to impose regulatory effects on immune responses [80,81,82]. By degrading target mRNAs or inhibiting translation, exosomal ncRNAs finely tune protein production essential for maintaining immune homeostasis. For example, exosomes containing miR-181a specifically target Egr2 mRNA in T cells, which disrupts Egr2-mediated signaling pathways critical for T cell development and function [83].

Exosomal ncRNAs significantly influence inflammatory pathways, acting as amplifiers or suppressors depending on the delivery context and recipient cell state [84]. In rheumatoid arthritis, miR-326, derived from immune cells, enhances pro-inflammatory cytokine production by targeting Id1, promoting Th17 cell differentiation [85]. Conversely, exosomal miR-223 has demonstrated protective effects in acute inflammation by suppressing macrophage activation [86]. For example, a recent study showed that manipulating exosomal miR-223 could effectively reduce inflammation in animal models of osteoarthritis [87]. MiR-223 achieves this by targeting Stat3, which reduces pro-inflammatory cytokines, thereby enhancing its protective mechanism [86].

In neurodegenerative conditions, exosomal ncRNAs regulate neuroinflammatory processes. For instance, exosomal miR-146a is implicated in modulating inflammatory pathways in microglia, influencing neuroinflammation associated with Alzheimer’s disease [88]. As mentioned above, miR-146a suppresses IRAK1 and TRAF6 signaling, dampening NF-κB activation in microglial cells, which switches microglial phenotypes to resist pathological processes and cognitive degradation [79].

Exosomal ncRNAs represent a critical axis in regulating immune responses and inflammatory pathways. Their diverse roles underscore the complexity of immune modulation, highlighting their potential for therapeutic exploitation in various diseases characterized by immune dysregulation. Recent findings emphasize the potential of exosomal ncRNAs as biomarkers and therapeutic agents, with specific examples like miR-223 and miR-146a showing promise in preclinical studies [89, 90].

Exosome-mediated immune dysregulation in autoimmune pathogenesis

The burgeoning field of exosome research reveals substantial insights into their involvement in AIDs, particularly through mediating intercellular communication and modulating immune processes [91, 92]. Exosomes, small extracellular vesicles, serve as carriers for proteins, lipids, and both coding and ncRNAs, significantly influencing AID pathogenesis. This section elucidates the involvement of exosomes in signaling pathways linked to inflammatory mediators, effects on innate immune cells, and impacts on adaptive immune responses [93].

Exosomal cargo as drivers of pro-inflammatory signaling

Exosomes actively participate in signaling pathways associated with inflammatory mediators, shaping the immune environment characteristic of AIDs [94]. They transport pro-inflammatory cytokines, chemokines, and signaling molecules, propagating inflammatory signals among various cell types [95]. In rheumatoid arthritis, exosomes from synovial fibroblasts have been shown to carry elevated levels of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, which enhance the inflammatory response when engulfed by other immune cells, thereby perpetuating disease-associated chronic inflammation [96, 97].

Dual roles of exosomal NcRNAs in autoimmune amplification

The role of exosomal microRNAs is significant in modulating inflammatory signaling pathways. For example, exosomal miR-155 is frequently upregulated in systemic lupus erythematosus and multiple sclerosis; it targets Suppressor of Cytokine Signaling 1 (SOCS1), enhancing signaling through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway [98, 99]. This pathway is crucial in SLE pathogenesis [100]. Moreover, a recent study reported that miR-21 could modulate macrophage polarization in type 1 diabetes, promoting a pro-inflammatory state [101]. Moreover, miR-223 modulates innate immune responses, influencing cytokine production and immune cell differentiation [102]. On the other hand, it has been demonstrated that miR-125b contributes to the regulation of inflammatory processes by affecting pro-inflammatory cytokine production [103]. Additionally, miR-124 has been shown to suppress immune cell activity and reduce pro-inflammatory mediators, demonstrating anti-inflammatory effects [104]. MiR-31 is linked to the regulation of inflammation in response to stimuli, whereas miR-34a affects inflammatory signaling pathways by targeting specific mediators [105, 106]. Collectively, these exosomal miRNAs offer insights into the complex regulation of inflammation and hold therapeutic potential for inflammatory diseases [107].

Recently, it has been showed that exosomes derived from T cells of patients with relapsing-remitting MS exhibited elevated levels of miR-326, a miRNA previously implicated in promoting Th17 differentiation [108]. This suggests that miR-326 can actively contribute to the inflammatory response characteristic of MS by enhancing pathways that lead to immune activation and tissue damage. The altered expression of this miRNA in exosomes not only highlights its potential role in MS pathogenesis but also positions it as a prospective biomarker for disease activity and prognosis.

In examining the fluctuating expression of miRNAs across disease phases, recent studies have illuminated their associations with inflammation and cognitive function in MS [109]. The differential expression of miRNA, notably miR-155 and miR-301a, correlates with clinical parameters indicative of disease activity and neuropsychiatric states such as depression. Lower levels of these miRNAs during remission phases suggest a potential relationship between their expression and regulatory mechanisms governing immune tolerance and psychological health in MS patients. The presence of such correlations indicates that exosomal miRNAs might serve as valuable biomarkers for not only tracking disease progression but also for tailoring interventions aimed at mitigating cognitive deficits associated with MS. The utility of exosomal miRNAs in diagnostic and therapeutic applications is further supported by findings from cerebrospinal fluid (CSF) studies, where increased levels of specific miRNAs such as miR-21 and miR-146a/b were correlated with active inflammatory lesions [110]. These miRNAs may act as candidates for monitoring disease activity and response to treatment due to their ability to reflect ongoing inflammatory processes in the CNS. The identification of these miRNA profiles reinforces the notion that they could serve crucial roles in both the diagnosis and progression monitoring of MS, providing a non-invasive approach to evaluating disease status.

The role of exosomal miRNAs in regulating inflammation in rheumatoid arthritis (RA) is highlighted across various studies, each contributing insights into different mechanisms and potential therapeutic applications. For example, exosomal miR-150-5p, demonstrates its ability to modulate inflammation by targeting matrix metalloproteinase 14 (MMP14) and VEGF in fibroblast-like synoviocytes (FLSs). MSC-derived exosomes containing miR-150-5p can effectively decrease FLS migration and invasion, thereby mitigating joint damage associated with RA [111]. The therapeutic potential of this exosomal miRNA underscores the possibility of engineering exosomes as a delivery vehicle for anti-inflammatory agents in RA treatment. In this context, miR-204-5p is another important exosomal miRNA significantly downregulated in RA patients and collagen-induced arthritis (CIA) models [112]. The decrease in miR-204-5p levels correlates with heightened inflammatory responses in FLSs, highlighting the intricate communication between immune cells and synovial fibroblasts in RA’s pathogenesis [112]. The therapeutic implications of restoring miR-204-5p levels suggest a strategy complementary to that of targeting MMP14 and VEGF via miR-150-5p.

In one study, the lncRNA NEAT1 was shown to be upregulated in exosomes derived from peripheral blood mononuclear cells (PBMCs) of RA patients [113]. The research revealed that NEAT1 can inhibit the expression of miR-23a, leading to the upregulation of MDM2, which, in turn, negatively affects Sirtuin 6 (SIRT6) levels. This cascade results in enhanced inflammatory responses and FLS proliferation. Importantly, the downregulation of NEAT1 or the overexpression of miR-23a impeded the deterioration of RA in murine models, suggesting that NEAT1 and the miR-23a/MDM2/SIRT6 axis offer potential therapeutic targets in RA treatment. This study reinforces the concept that lncRNAs can modulate miRNA activity, affecting cellular responses in inflammatory conditions such as RA. Further elucidating the role of lncRNAs, another study investigated the lncRNA HOTTIP in RA, revealing its upregulation in RA synovial fibroblasts and its negative regulation of miR-1908-5p, leading to the activation of STAT3, a known facilitator of pro-inflammatory responses [114]. In vivo experiments demonstrated that overexpression of HOTTIP exacerbated inflammation in RA mice, further indicating that HOTTIP contributes to the inflammatory milieu of RA through its regulation of key signaling pathways. This study emphasizes how exosomal lncRNAs can influence inflammatory pathways and cellular interactions, reinforcing the potential for targeting these molecules in RA therapy. The evidence presented in a recent study demonstrated the presence of HAND2-AS1 in exosomes from mesenchymal stem cells and its role in inhibiting RA-FLS activation via the miR-143-3p/TNFAIP3/NF-κB axis [115]. The study illuminated how HAND2-AS1 can act as a sponge for miR-143-3p, thereby enhancing TNFAIP3 expression, which negatively regulates NF-κB signaling. This regulatory network indicates the potential for using MSC-derived exosomal lncRNAs as therapeutic agents to modulate immune responses and mitigate inflammation in RA.

Expanding on the therapeutic potential of mesenchymal stem cells, Huang et al. [116] emphasize the significance of miR-223 in exosomes derived from bone marrow mesenchymal stem cells (BMSCs). They reported that miR-223 suppresses the NLRP3 inflammasome pathway in macrophages, exhibiting another layer of anti-inflammatory regulation within the context of RA [116]. This finding connects to the earlier studies by reinforcing the notion that MSCs can generate exosomes containing various miRNAs (including miR-150-5p and miR-223) that collectively exert immunomodulatory effects, thus presenting a multipronged therapeutic approach to RA. Furthermore, MiR-320a delivered through MSC-derived exosomes was shown to suppress CXCL9, another important mediator in RA’s inflammatory milieu [117]. The study suggests that enhancing miR-320a levels may be an effective strategy to combat FLS activation and migration, consistent with the other studies’ findings that emphasize the role of miRNAs in modulating inflammatory responses through direct targeting of inflammatory mediators [117]. Overall, these studies collectively reinforce the understanding that exosomal miRNAs from various cellular origins significantly influence inflammation in RA. The interconnected roles of miR-150-5p, miR-204-5p, miR-223, miR-320a, and miR-17 illustrate a complex regulatory network while providing a compelling rationale for developing exosome-based therapies that can deliver these miRNAs to affected tissues in RA, thereby enhancing therapeutic efficacy and potential patient outcomes.

Exosome-dependent crosstalk between innate and adaptive immunity

Exosomes profoundly affect innate immune cells, which are crucial in initiating and maintaining autoimmune responses. In lupus, exosomes from activated B cells can transfer their contents to dendritic cells, enhancing antigen-presenting capabilities and subsequently leading to robust T cell activation skewed toward autoimmunity [118, 119]. Studies indicate that exosomal miRNAs from lupus patients can promote monocyte differentiation into macrophages, adopting an M1-like pro-inflammatory phenotype [120]. Moreover, exosomes derived from mesenchymal stem cells (MSCs) have emerged as promising therapeutic agents in the management of autoimmune diseases, particularly MS [121]. By influencing the polarization of microglia—resident immune cells in the CNS—MSC-derived exosomes can tilt the balance from a pro-inflammatory M1 phenotype towards a protective M2 phenotype. This modulation is crucial for reducing inflammation and facilitating remyelination, as demonstrated in experimental models of EAE, which closely mirror MS pathology. Another study indicated that the expression of exosomal miR-122-5p was significantly correlated with disease activity indices, such as the systemic lupus erythematosus disease activity index (SLEDAI) and levels of double-stranded DNA (dsDNA) antibodies [122]. Inhibition of miR-122-5p led to a considerable reduction in M1 macrophage polarization, suggesting that exosomal miR-122-5p is instrumental in the inflammatory processes associated with SLE. The targeted downregulation of FOXO3 by miR-122-5p enhances the NF-κB pathway’s activation, which is critical for the pro-inflammatory response in macrophages, thereby exacerbating the clinical manifestations of lupus nephritis [122]. Such findings emphasize the importance of exosomal miRNAs as mediators of cross-talk between various immune cells and underscore their potential as novel biomarkers and therapeutic targets for managing autoimmune inflammation in SLE.

Li et al. [123] recently found that small extracellular vesicles (sEVs) derived from human umbilical cord mesenchymal stem cells (hUC-MSC-sEVs) can reduce autoimmune dacryoadenitis by promoting M2 macrophage polarization and enhancing regulatory T cell (Treg) differentiation through the delivery of miR-100-5p. This mechanism leads to reduced inflammation and improved tissue repair in a rabbit model of Sjögren’s syndrome dry eye. Their results demonstrated that hUC-MSC-sEVs significantly shifted macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. miR-100-5p was identified as crucial for this polarization effect, as its inhibition reduced both M2 macrophage polarization and Treg generation. In autoimmune conditions like Sjögren’s syndrome, an excess of M1 macrophage activation contributes to chronic inflammation and tissue damage, highlighting the importance of promoting M2 macrophage activity [123]. Overall, the findings support the idea that exosomal miRNAs, especially miR-100-5p, play a significant role in mediating immune modulation via hUC-MSC-sEVs. This research points to the potential for developing new therapeutic strategies that leverage exosomal miRNAs for managing autoimmune diseases effectively. Further investigations may uncover additional pathways through which exosomal miRNAs can be applied clinically.

Furthermore, exosomal miRNAs released from macrophages have been shown to exacerbate intestinal barrier dysfunction in inflammatory bowel disease (IBD) by regulating TMIGD1 through miR-223 [124]. Elevated levels of miR-223 in macrophage-derived exosomes were linked to increased intestinal inflammation, highlighting how exosomes can influence both innate and adaptive immune responses in the context of autoimmune diseases [124].

Exosomal miRNAs derived from bone marrow-derived mesenchymal stem cells (BMMSCs) play a pivotal role in modulating macrophage polarization and inflammation in systemic lupus erythematosus (SLE), as demonstrated by recent findings [125]. In a pristane-induced murine lupus nephritis model, BMMSC-derived exosomes significantly alleviated renal pathology by promoting the anti-inflammatory polarization of macrophages, characterized by upregulated CD206, B7H4, CD138, and arginase-1 (Arg-1), alongside downregulated pro-inflammatory markers such as CD86 and inducible nitric oxide synthase (iNOS) [125]. Mechanistically, these exosomes delivered miR-16 and miR-21, which targeted PDCD4 and PTEN in macrophages, respectively, to suppress pro-inflammatory signaling pathways and enhance efferocytosis activity [125]. This polarization shift correlated with increased secretion of anti-inflammatory cytokines (IL-10, TGF-β) and chemokine CCL20, facilitating the recruitment of IL-17 + regulatory T (Treg) cells, which contributed to immune tolerance [125]. Critically, depletion of miR-16 and miR-21 in exosomes abolished their therapeutic effects, underscoring the miRNAs’ essential role in mitigating SLE progression [125]. These findings highlight exosomal miRNAs as key mediators of macrophage reprogramming and propose a novel therapeutic strategy for autoimmune diseases by harnessing exosome-mediated miRNA transfer to restore immune homeostasis.

In multiple sclerosis, exosomal miR-230 has been linked to myeloid-derived suppressor cell (MDSC) modulation, expanding the population of IL-10-producing cells that can further influence T cell responses [126]. Exosomes from peripheral blood mononuclear cells in RA can modify macrophage behavior, heightening pro-inflammatory cytokine production and leading to increased joint tissue damage [127].

Exosomes also significantly influence adaptive immune responses, notably by amplifying autoreactive T cell activation [128]. They can carry autoantigens and facilitate their presentation to naïve T cells [129]. For example, exosomes from monosodium urate crystals stimulate dendritic cells to present inflammatory signals, promoting T cell differentiation into Th17 cells, which are profoundly linked to arthritis pathogenesis [130, 131].

In AIDs like psoriasis, exosomal miR-146a has been associated with exacerbated inflammation by promoting NF-κB signaling pathway activation in keratinocytes and T cells, further perpetuating the cycle of inflammation [132]. Moreover, exosomes from patients with psoriatic arthritis have been shown to contain fragments of the IL-17 A gene, indicating possible roles in the heightened inflammatory state observed in these patients [133, 134].

The manipulation of T cell activation through exosomes also manifests in conditions such as SLE [135]. Exosomal transport of antigenic material can facilitate autoantigen presentation to T cells, promoting their activation and differentiation into autoreactive effector cells. Exosomes from SLE patients carry high levels of anti-nuclear antibodies (ANA), a hallmark of the disease, indicating their contribution to autoantigen recognition and T cell activation [136, 137]. Furthermore, the exosomal miRNA let-7i presents a distinct mechanism of action, specifically inhibiting the differentiation of regulatory T cells (Tregs) that are essential for maintaining immune homeostasis [138]. The overexpression of let-7i in exosomes from MS patients appears to downregulate receptors critical for Treg function, such as IGF1R and TGFBR1, thereby impairing the Tregs’ ability to modulate inflammation effectively. This dysregulation can significantly impact the pathogenesis of MS by fostering an imbalance between regulatory and inflammatory T cells. Recognizing the intricate interplay between exosomal miRNAs and Treg functionality paves the way for novel therapeutic strategies aimed at restoring immune balance in MS patients. Following this line of inquiry, another study focused on the role of exosomal RNA fragments derived from MSCs, specifically tsRNA-21,109, which was found to suppress M1 macrophage polarization, a key contributor to systemic lupus erythematosus (SLE) pathology [139]. The findings demonstrated that MSC-derived exosomes containing tsRNA-21109 significantly reduced pro-inflammatory cytokine production associated with M1 macrophages while promoting an M2 phenotype. This highlights the capacity of exosomal RNA fragments to regulate immune responses and suggests their utility in therapeutic applications for autoimmune diseases, such as RA and SLE.

In type 1 diabetes mellitus (T1DM), miR-25 derived from MSCs has been shown to inhibit T cell migration into the pancreatic islets, thereby alleviating inflammation and protecting β-cell function [140]. This effect is mediated by a significant reduction in the expression of the chemokine receptor CXCR3 on T cells, which is crucial for the recruitment of these cells to inflamed tissues [140]. The ability of exosomal miR-25 to downregulate CXCR3 highlights the potential of utilizing MSC-derived exosomes as a therapeutic strategy to counteract the pathological behaviors of immune cells in autoimmune conditions.

In SLE, marked by dysregulated immune responses, exosomes derived from umbilical cord blood mesenchymal stem cells (UC-BSCs) have been found to modulate the balance of T helper 17 (Th17) and regulatory T (Treg) cells [141]. Notably, exosomal miR-19b plays a pivotal role in this process by targeting KLF13, a transcription factor implicated in T cell differentiation. The UC-BSC-derived exosomes increase miR-19b levels in PBMCs from SLE patients, thereby restoring the Treg/Th17 balance and reducing inflammation [141]. This regulatory action emphasizes the potential for exosomal miRNAs to influence immune cell behavior, offering new avenues for therapeutic intervention in autoimmune diseases like SLE. Moreover, exosomal miRNAs are implicated in the pathogenesis of Sjögren’s syndrome (SS), a condition characterized by systemic manifestations and sicca symptoms. Research has shown that secretory miR-29a-3p from SHED-derived exosomes can suppress Th1 cell responses by targeting T-bet, a transcription factor essential for Th1 differentiation [142]. By lowering Th1 response and reducing inflammatory cytokines, SHED-derived exosomes may ameliorate SS symptoms, demonstrating how exosomal miRNAs can act as key regulators in autoimmune processes.

Expanding on the role of exosomes in inflammation, recent findings regarding Behçet’s uveitis (BU) suggest that plasma-derived exosomal miR-19b-3p facilitates a Treg/Th17 cell imbalance by downregulating CD46, a crucial protein involved in Treg induction and IL-10 production [143]. The dysregulated expression of miR-19b-3p in exosomes from patients with active BU not only leads to increased Th17 cell differentiation but also hinders the development of Tregs, thus contributing to disease progression [143]. This illustrates the intricate relationship between exosomal miRNAs and immune dysregulation in autoimmune diseases.

Exosomes serve as integral mediators in AIDs, influencing inflammatory signaling, modulating innate immune cell functions, and shaping adaptive immune responses [144]. Their capacity to facilitate communication among immune cells and disseminate inflammatory mediators underscores their critical role in AID pathogenesis [94]. Insights into exosomal biology may pave the way for novel therapeutic strategies targeting exosomal components to restore immune balance and mitigate the detrimental effects of autoimmunity [145].

Microglial activation and exosome dynamics in neuroinflammation

Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining homeostasis within the brain and spinal cord [146]. Strategically positioned to respond to various stimuli through activation, microglial response can become dysregulated in neuroinflammatory conditions [147]. Recent research advancements indicate that exosomes, small extracellular vesicles secreted by various cell types, significantly mediate communication between microglia and other CNS cells [148]. This section explores the relationship between exosomes and microglial activation, examining the role of exosomal components in glial cell behavior modulation and their implications for neuroinflammatory disorders [149].

The interplay between exosomes and microglial activation

Exosomes released from both microglia and other cell types facilitate intercellular communication, particularly during neuroinflammation [150, 151]. Studies demonstrate that microglial activation stimulates exosome release containing pro-inflammatory mediators, including cytokines, chemokines, and bioactive lipids. Activated microglia release exosomes loaded with TNF-α and IL-1β, critical drivers of neuroinflammation. The presence of these pro-inflammatory factors in exosomes allows for the amplification of inflammatory signals and can influence neighboring neurons and glial cells [152, 153].

Moreover, microglial exosomes contribute to clearing cellular debris and misfolded proteins that accumulate in pathological states [154, 155]. In Alzheimer’s disease, for instance, microglial-derived exosomes carrying amyloid-beta (Aβ) peptides may promote neurotoxic aggregate spread, contributing to synaptic dysfunction and neuroinflammation. The balance between protective and damaging exosomal cargo becomes crucial for overall neural health [156,157,158].

MiRNAs have emerged as potential modulators of microglial activation, suggesting therapeutic avenues for preventing neurodegeneration [159]. Ni et al. [160] have demonstrated that intracerebroventricular injection of let-7c-5p mimics diminished infarction volume and neurological deficits by inhibiting microglial activation through caspase-3 regulation [160]. Additionally, miR-203 directly targets MyD88 in microglia, repressing NF-κB signaling and preventing neuronal injury [161]. Similarly, miR-145-5p binds to Nurr1 mRNA to alleviate neuronal injury in ischemia models [162]. MiR-199b inhibits the IKKβ-NF-κB pathway in spinal cord injury, while miR-424 treatment reduces brain edema and infarction size after ischemia by repressing microglial activation [163].

Other notable examples include miR-7, which ameliorates microglial activation in PD models, and miR-27a, which regulates inflammatory cytokine production through TLR4/IRAK4 inhibition [164, 165]. Furthermore, miR-181c also targets TLR4 to mitigate neuroinflammation in hypoxic conditions. In amyotrophic lateral sclerosis (ALS), miR-125b enhances NF-κB activation and microglial function, while anti-miR-143 promotes microglial survival in methamphetamine-induced neurotoxicity [159]. Several microRNAs (miRNAs), including miR-146b, miR-29b, let-7a/b, miR-27b, miR-21, miR-210, and miR-155, exhibit upregulated expression in ALS. Additionally, elevated levels of miR-9 have been observed specifically in the ventral horn of the spinal cord, the site of neurodegeneration associated with this disease. Notably, among the aforementioned miRNAs, miR-155, miR-146b, and miR-125b are recognized as integral constituents of the innate immune system [166,167,168]. Lastly, miR-146a has shown potential in restoring cognitive function by targeting specific inflammation-related proteins [159, 169].

Microglial activation state also influences the composition of secreted exosomes. Quiescent microglia primarily release exosomes loaded with neuroprotective factors and anti-inflammatory cytokines, whereas activated microglia predominantly secrete exosomes with cytotoxic components that heighten inflammation and induce neuronal cell death [170, 171]. Recent findings have shown that exosomes from alternatively activated microglia can promote repair and regeneration, thereby highlighting their dual role [172, 173].

Impact of microglial-derived exosomes on other glial cells

The contents of microglial exosomes profoundly affect neighboring glial cells, including astrocytes and oligodendrocytes [174]. Exosomal miRNAs regulate astrocyte functions by influencing their transition between pro-inflammatory and neuroprotective states. For example, exosomal miR-223 released from activated microglia has been shown to increase the expression of inflammatory factors within astrocytes, illustrating how microglial exosomes can perpetuate neuroinflammatory processes [175, 176]. Lauforcade et al. suggested that exosomes containing miRNAs from astrocytes, such as miR-26a, are compromised in various CNS disorders, potentially affecting neuronal structure and synaptic communication [177]. Additionally, Xin et al. indicated that exosomes derived from multipotent mesenchymal stromal cells (MSCs) overexpressing miR-33b can enhance neural plasticity and facilitate functional recovery following a stroke in rats. This effect appears linked to the stimulated secondary release of exosomes from astrocytes, which promote neurite growth [178].

Exosomal contents can also influence oligodendrocyte functions, particularly relevant in demyelinating disorders like MS. Research indicates that exosomes derived from activated microglia may contain proteins that disrupt oligodendrocyte maturation and myelination, leading to impaired neuronal function and increased neurodegeneration. Conversely, exosomes from quiescent microglia may carry neuroprotective factors that promote oligodendrocyte survival and remyelination, underscoring the importance of exosomal content in modulating glial behavior [153, 179, 180].

During microglial activation, exosomes may carry various receptors, signaling molecules, and proteins that can directly interact with neighboring cells. Microglial-derived exosomes can transfer Fas ligand (FasL) to induce apoptosis in neurons, highlighting their role in promoting neuroinflammation and cell death, which further contributes to neurological dysfunction [149, 181]. Furthermore, Song et al. showed that exosomes derived from M2 microglia can reduce ischemic brain damage and enhance neuronal survival through exosomal miR-124 and its downstream target USP14, indicating the therapeutic potential of exosomes from M2 microglia in ischemic stroke [182].

Implications for neuroinflammatory disorders

The interplay between exosomal signaling and microglial activation has significant implications for neuroinflammatory disorders, such as Alzheimer’s disease, Parkinson’s disease (PD), and MS. In Alzheimer’s disease, the accumulation of amyloid-beta plaques induces chronic microglial activation, leading to increased exosome secretion that propagates inflammatory signals, exacerbating neuronal damage. Additionally, microglial-derived exosomes have been implicated in tau protein dissemination, contributing to the spread of tau pathology in the brain [181, 183]. Elevated levels of the miRNA let-7 have been observed in patients with Alzheimer’s disease (AD). It has been postulated that let-7 activates the RNA-sensing Toll-like receptor 7 (TLR7), thereby contributing to neurodegenerative processes in these individuals. Experimental studies utilizing TLR7 knockout (KO) mice have demonstrated that these mice exhibit resistance to neurodegenerative factors. However, the precise mechanism by which let-7 miRNA accesses the endosomal TLR7 receptor within the central nervous system (CNS) remains uncertain. Notably, investigations concerning metastatic gastric cancer have revealed that let-7 miRNA is released into the extracellular environment through exosomal transport mechanisms [184, 185].

In PD, the expression levels of let-7, alongside miR-205 and miR-184, have been correlated with the expression of alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2), two genes significantly associated with PD [186]. A recent study has demonstrated that let-7 represses α-syn expression and is downregulated in models of PD. Furthermore, an increasing body of evidence suggests a significant relationship between PD and TLRs. It has recently been shown that extracellular α-synuclein enhances the expression of TLR1, TLR2, TLR3, and TLR7 [185, 187, 188]. In the context of PD, microglial exosomes are implicated in the disease’s pathogenesis; exosomes secreted from activated microglia carry pro-inflammatory cytokines that can induce dopaminergic neuron death, thus participating in the neurodegenerative processes characteristic of PD [189, 190]. Moreover, studies suggest that exosomal cargo may serve as potential biomarkers for assessing disease progression. Elevated levels of certain exosomal miRNAs, including miR-29a, miR-125b-5p, and miR-153-3p, in the cerebrospinal fluid of PD patients have been associated with disease severity and neuronal loss, marking a potential avenue for therapeutic intervention and diagnostic purposes [191,192,193,194].

MS exemplifies the dual role of microglial exosomes. In this context, exosomes can contribute to the demyelination process by transferring inflammatory mediators that disrupt the function and survival of oligodendrocytes. Conversely, there is significant potential for utilizing exosomes as therapeutic vehicles. Exosomes engineered to contain anti-inflammatory agents or neuroprotective factors may offer innovative strategies for mitigating neuroinflammation while promoting recovery in demyelinating diseases [195]. Manna et al. [196]. examined exosome-associated miRNAs in MS patients both prior to and following interferon-beta (IFN-β) therapy. They discovered that 14 miRNAs (miR-26a-5p, miR-142-3p, miR-486-5p, miR-451a, miR-146a-5p, miR-let-7b-5p, miR-19b-3p, miR-15b-3p, miR-320b, miR-122-5p, miR-215-5p, miR-23a-3p, miR-320d, and miR-223-3p) were significantly downregulated, whereas two miRNAs (miR-22-3p and miR-660-5p) were notably upregulated in relapsing-remitting MS patients treated with IFN-β who responded to therapy, compared to those who did not respond. Furthermore, a serum miRNA panel was identified that could be useful for monitoring responses to IFN-β treatment. Overall, these findings suggest that profiling circulating exosome-associated miRNAs may serve as a readily detectable biomarker for both the disease and treatment efficacy [196].

Overall, the relationship between microglial activation and exosomes is pivotal in neuroinflammatory disorders. Exosomes serve as key mediators of neuroinflammation, carrying bioactive molecules that influence glial cell behavior and neuronal homeostasis. Understanding the dynamics of microglial-derived exosomes and their impact on CNS health may pave the way for innovative therapeutic strategies aimed at ameliorating neuroinflammation and protecting neuronal integrity in various neurodegenerative diseases [197, 198]. As research progresses, the exploration of exosomal biology promises to unveil potential targets for intervention, offering new hope for patients suffering from neuroinflammatory disorders.

Conclusion and future perspective

Exosomes have emerged as pivotal players in the pathogenesis of AIDs, driving immune dysregulation and chronic inflammation through their role as intercellular messengers. This review has underscored how exosomal ncRNAs—such as miR-155 in systemic lupus erythematosus, miR-326 in rheumatoid arthritis, and miR-146a across multiple AIDs—orchestrate immune cell communication and modulate inflammatory pathways signaling. These ncRNAs exhibit a dual nature, amplifying disease states (e.g., miR-155 targeting SOCS1 to enhance JAK-STAT signaling) while also offering therapeutic promise (e.g., miR-146a suppressing inflammation and enhancing Treg function). Additionally, in neuroinflammatory AIDs, exosomal ncRNAs like miR-223 and miR-124 regulate microglial activation, influencing neurodegenerative processes.

The therapeutic potential of exosomes lies in their ability to deliver bioactive molecules and serve as biomarkers. Engineering exosomes to carry anti-inflammatory agents or silence pathogenic ncRNAs (e.g., miR-326) could reprogram immune responses, offering targeted treatments for AIDs. Moreover, exosomal cargo profiles—such as elevated miR-155 in SLE or miR-29a in Parkinson’s disease—enable early diagnosis and personalized therapy, aligning with precision medicine goals. However, challenges persist, including incomplete understanding of exosome biogenesis, cargo sorting, and uptake mechanisms, as well as the lack of standardized isolation techniques, which hinder clinical translation.

Future research should prioritize elucidating the molecular pathways governing ncRNA packaging into exosomes and developing technologies for real-time in vivo tracking of exosomal dynamics. Interdisciplinary efforts combining molecular biology, nanotechnology, and bioinformatics could yield synthetic exosomes with enhanced stability and specificity or decode complex ncRNA-immune interactions. In neuroinflammation, exploring exosomal delivery of neuroprotective factors (e.g., miR-124 to quiescent microglia) could mitigate neuronal damage in diseases like multiple sclerosis or Alzheimer’s.

Autophagy is a cellular process where cells degrade and recycle damaged components to maintain homeostasis, crucial in neurons for clearing misfolded proteins and maintaining function. Exosomes by carrying molecules like ncRNAs, which can regulate inflammatory pathways [199]. Besides, the intersection of these pathways is supported by general research, indicating that autophagy can influence exosome biogenesis and cargo, particularly through shared endosomal pathways and molecular components like ALIX and ESCRT complexes. It has been reported that autophagy and exosomal pathways are known to intersect in maintaining neuronal cellular homeostasis crosstalk between exosomes and autophagy [200,201,202]. Recent studies have highlighted the role of autophagy in AIDs affecting the nervous system, such as Myasthenia Gravis, multiple sclerosis, and the involvement of brain-derived neurotrophic factor (BDNF) signaling in MS [200,201,202]. Some reviews have prioritized the role of exosomal non-coding RNAs (ncRNAs) in AIDs. Therefore, future research should investigate how autophagy influences the cargo of exosomes, particularly ncRNAs, in these diseases to uncover novel mechanisms and potential therapeutic targets.

By addressing these gaps, exosome-based strategies stand poised to transform AID management. From disrupting chronic inflammation to restoring immune balance, these approaches promise innovative therapies and improved patient outcomes, redefining treatment paradigms for autoimmune and neuroinflammatory disorders.