# Extracellular vesicles in rheumatoid arthritis: emerging roles in progression, diagnosis, and therapeutic development

**Authors:** Qisong Liu, Lili He, Xiaomin Wu, Xiaohua Pan

PMC · DOI: 10.3389/fimmu.2026.1748591 · Frontiers in Immunology · 2026-02-10

## TL;DR

Extracellular vesicles (EVs) are important in rheumatoid arthritis (RA) progression, diagnosis, and treatment, offering potential for new biomarkers and therapies.

## Contribution

This review highlights the emerging roles of EVs in RA and their potential for clinical translation.

## Key findings

- EVs contribute to inflammation and tissue damage in RA through cell signaling.
- EVs from RA patients show altered profiles linked to disease activity.
- EVs can deliver bioactive molecules and serve as targeted therapeutic tools.

## Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that is pathologically defined by persistent synovitis and systemic inflammation. Currently, the clinical diagnosis and management of RA remain challenging, particularly with respect to early detection, the treatment of refractory cases, and ensuring long-term medication safety. Therefore, it is imperative to deepen our understanding of RA pathogenesis, identify specific biomarkers, and develop innovative therapeutic strategies. This review summarizes the roles and recent advances concerning extracellular vesicles (EVs) in RA progression, diagnosis, and therapeutic development. Research indicates that during RA development, joint-resident cells, immune cells, and relevant body fluids form a complex network in which EV-mediated signaling amplifies inflammatory responses and exacerbates tissue damage. Moreover, studies have shown that EVs isolated from synovial fluid and the circulation of RA patients exhibit significantly altered expression profiles, morphology, or subtype composition. These alterations are closely associated with disease activity, underscoring their potential as diagnostic biomarkers and tools for monitoring disease severity. Regarding therapy, EVs derived from diverse cellular sources have demonstrated promising therapeutic potential in RA. They not only carry bioactive molecules that can modulate RA-associated cells, but also serve as engineered delivery vehicles for targeted therapeutic interventions. In summary, EVs play multifaceted roles in the progression, diagnosis, and treatment of RA. Future research should focus on translating EV-related discoveries into clinical applications, thereby supporting the development of novel strategies for the precise diagnosis and management of RA.

## Linked entities

- **Diseases:** rheumatoid arthritis (MONDO:0008383), RA (MONDO:0005272)

## Full-text entities

- **Genes:** CRK (CRK proto-oncogene, adaptor protein) [NCBI Gene 1398] {aka CRKII, p38}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, TIMP1 (TIMP metallopeptidase inhibitor 1) [NCBI Gene 7076] {aka CLGI, EPA, EPO, HCI, TIMP, TIMP-1}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, Mir451a (microRNA 451a) [NCBI Gene 723870] {aka Mir451, Mirn451, mir-451a, mmu-mir-451, mmu-mir-451a}, MERTK (MER proto-oncogene, tyrosine kinase) [NCBI Gene 10461] {aka MER, RP38, Tyro12, c-Eyk, c-mer}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, Ccni (cyclin I) [NCBI Gene 12453], Sgk1 (serum/glucocorticoid regulated kinase 1) [NCBI Gene 20393] {aka Sgk}, SOX9 (SRY-box transcription factor 9) [NCBI Gene 6662] {aka CMD1, CMPD1, ENH13, SRA1, SRXX2, SRXY10}, MIR223 (microRNA 223) [NCBI Gene 407008] {aka MIRN223, miRNA223, mir-223}, MIR335 (microRNA 335) [NCBI Gene 442904] {aka MIRN335, hsa-mir-335, miRNA335, mir-335}, CCR5 (C-C motif chemokine receptor 5) [NCBI Gene 1234] {aka CC-CKR-5, CCCKR5, CCR-5, CD195, CKR-5, CKR5}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, TOB1 (transducer of ERBB2, 1) [NCBI Gene 10140] {aka APRO5, APRO6, PIG49, TOB, TROB, TROB1}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, FAS (Fas cell surface death receptor) [NCBI Gene 355] {aka ALPS1A, APO-1, APT1, CD95, FAS1, FASTM}, CDAN1 (codanin 1) [NCBI Gene 146059] {aka CDA1, CDAI, CDAN1A, DLT, PRO1295}, PFKP (phosphofructokinase, platelet) [NCBI Gene 5214] {aka ATP-PFK, PFK-C, PFK-P, PFKF}, TNFSF11 (TNF superfamily member 11) [NCBI Gene 8600] {aka CD254, ODF, OPGL, OPTB2, RANKL, TNLG6B}, PDK4 (pyruvate dehydrogenase kinase 4) [NCBI Gene 5166], CRKL (CRK like proto-oncogene, adaptor protein) [NCBI Gene 1399], Pias3 (protein inhibitor of activated STAT 3) [NCBI Gene 229615] {aka Pias3l}, CD14 (CD14 molecule) [NCBI Gene 929], IL1RN (interleukin 1 receptor antagonist) [NCBI Gene 3557] {aka CRMO2, DIRA, ICIL-1RA, IL-1RN, IL-1ra, IL-1ra3}, Mir34a (microRNA 34a) [NCBI Gene 723848] {aka Mirn34a, mir-34a, mmu-mir-34a}, MIR23A (microRNA 23a) [NCBI Gene 407010] {aka MIRN23A, hsa-mir-23a, miRNA23A, mir-23a}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, CDO1 (cysteine dioxygenase type 1) [NCBI Gene 1036] {aka CDO-I}, SELP (selectin P) [NCBI Gene 6403] {aka CD62, CD62P, GMP140, GRMP, LECAM3, PADGEM}, KRAS (KRAS proto-oncogene, GTPase) [NCBI Gene 3845] {aka 'C-K-RAS, C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A}, PRTN3 (proteinase 3) [NCBI Gene 5657] {aka ACPA, AGP7, C-ANCA, CANCA, MBN, MBT}, TNFSF12 (TNF superfamily member 12) [NCBI Gene 8742] {aka APO3L, DR3LG, TNF12, TNLG4A, TWEAK}, CD69 (CD69 molecule) [NCBI Gene 969] {aka AIM, BL-AC/P26, CLEC2C, EA1, GP32/28, MLR-3}, MPIG6B (megakaryocyte and platelet inhibitory receptor G6b) [NCBI Gene 80739] {aka C6orf25, G6b, G6b-B, NG31, THAMY}, CSF1 (colony stimulating factor 1) [NCBI Gene 1435] {aka CSF-1, MCSF, PG-M-CSF}, CREB1 (cAMP responsive element binding protein 1) [NCBI Gene 1385] {aka CREB, CREB-1}, NEAT1 (nuclear paraspeckle assembly transcript 1) [NCBI Gene 283131] {aka LINC00084, NCRNA00084, TP53LC15, TncRNA, VINC}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, LYVE1 (lymphatic vessel endothelial hyaluronan receptor 1) [NCBI Gene 10894] {aka CRSBP-1, HAR, LYVE-1, XLKD1}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, MMRN1 (multimerin 1) [NCBI Gene 22915] {aka ECM, EMILIN4, GPIa*, MMRN}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, MIR124-1 (microRNA 124-1) [NCBI Gene 406907] {aka MIR124A, MIR124A1, MIRN124-1, MIRN124A1, mir-124-1}, Kras (KRAS proto-oncogene, GTPase) [NCBI Gene 24525] {aka K-ras, Kras2, c-Ki-ras, p21}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], BMP1 (bone morphogenetic protein 1) [NCBI Gene 649] {aka OI13, PCOLC, PCP, TLD}, WTAP (WT1 associated protein) [NCBI Gene 9589] {aka Mum2}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, CIAPIN1 (cytokine induced apoptosis inhibitor 1) [NCBI Gene 57019] {aka Anamorsin, CIAE2, DRE2, PRO0915}, FPR2 (formyl peptide receptor 2) [NCBI Gene 2358] {aka ALX, ALXR, FMLP-R-II, FMLPX, FPR2A, FPRH1}, CD40LG (CD40 ligand) [NCBI Gene 959] {aka CD154, CD40L, HIGM1, IGM, IMD3, T-BAM}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, PRDM1 (PR/SET domain 1) [NCBI Gene 639] {aka BLIMP-1, BLIMP1, PRDI-BF1}, Atf2 (activating transcription factor 2) [NCBI Gene 11909] {aka Atf-2, CRE-BP, Creb2, D130078H02Rik, Tg(Gzma-Klra1)7Wum, mXBP}, Cxcl9 (C-X-C motif chemokine ligand 9) [NCBI Gene 17329] {aka CMK, Mig, MuMIG, Scyb9, crg-10}, IKBKB (inhibitor of nuclear factor kappa B kinase subunit beta) [NCBI Gene 3551] {aka IKK-2, IKK-beta, IKK2, IKKB, IMD15, IMD15A}, MIR146A (microRNA 146a) [NCBI Gene 406938] {aka MIRN146, MIRN146A, miR-146a, miRNA146A}
- **Diseases:** arthritis (MESH:D001168), RA (MESH:D001172), immune dysfunction (MESH:D007154), synovitis (MESH:D013585), T (MESH:D001260), axSpA (MESH:D000089183), bone loss (MESH:D001847), bone erosion (MESH:D014077), Wilms' (MESH:D009396), toxicity (MESH:D064420), joint (MESH:D007592), DMARDs (MESH:D012216), G-MDSCs (OMIM:601308), mucosal injury (MESH:D052016), articular destruction (MESH:D008105), synovial hyperplasia (MESH:D006965), chronic (MESH:D002908), inflammation (MESH:D007249), osteosarcoma (MESH:D012516), pain (MESH:D010146), gout (MESH:D006073), G (MESH:D004314), Sjogren's syndrome (MESH:D012859), CIA (MESH:D001169), swelling (MESH:D004487), autoimmune (MESH:D001327), obesity (MESH:D009765), OCs (MESH:D001862), hyperemia (MESH:D006940), arthritic (MESH:D015535), OA (MESH:D010003), bone and cartilage destruction (MESH:D002357), hypoxia (MESH:D000860)
- **Chemicals:** CII (-), curcumin (MESH:D003474), silica (MESH:D012822), Ru (MESH:D012428), dexamethasone (MESH:D003907), icariin (MESH:C056599), phosphatidylserine (MESH:D010718), Triptolide (MESH:C001899), LPS (MESH:D008070), docosahexaenoic acid (MESH:D004281), lipids (MESH:D008055), heparin (MESH:D006493), anthocyanins (MESH:D000872), ROS (MESH:D017382), FA (MESH:D005492), EGCG (MESH:C045651), chondroitin sulfate (MESH:D002809), Prussian blue (MESH:C000170), BP (MESH:D010758), Rapamycin (MESH:D020123), CuS (MESH:C017846), water (MESH:D014867), MTX (MESH:D008727), M2 (MESH:C034584), betamethasone sodium phosphate (MESH:C028994), PGE2 (MESH:D015232), Fe2O3 (MESH:C000499), copper (MESH:D003300), cyclic citrullinated peptide (MESH:C487763), HA (MESH:D006820)
- **Species:** Tripterygium wilfordii (species) [taxon 458696], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986], Mus musculus (house mouse, species) [taxon 10090], Panax ginseng (Asiatic ginseng, species) [taxon 4054]
- **Mutations:** G12D, (AUC) of 0
- **Cell lines:** 293T — Homo sapiens (Human), Transformed cell line (CVCL_0063), FLS — Canis lupus familiaris (Dog), Spontaneously immortalized cell line (CVCL_AP75), BMSC — Oryctolagus cuniculus (Rabbit), Finite cell line (CVCL_B6BB)

## Full text

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## Figures

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## References

159 references — full list in the complete paper: https://tomesphere.com/paper/PMC12929417/full.md

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Source: https://tomesphere.com/paper/PMC12929417