The Role of Extracellular Vesicles in Synovial Injuries of Athletic Joints
Article Sidebar
Main Article Content
Abstract
Synovial membrane injury, which profoundly affects joint structure and function, plays a pivotal role in the progression of joint diseases. When manifest clinically as pain, inflammation, joint stiffness, or function impairment, such injuries may eventually advance to degenerative changes, cartilage damage, or arthritis, which significantly diminishes patients' quality of life. In the field of joint regenerative medicine, particularly concerning sports-related synovial membrane injuries, extracellular vesicles (EVs) released from damaged synovial cells have emerged as a key research focus. These vesicles not only serve as indicators of synovial damage and inflammation, but may also be integral to the underlying pathophysiological processes of these injuries. EVs can influence crucial biological processes such as inflammatory response, cell proliferation, and fibrosis. Additionally, bioactive molecules within these vesicles, i.e., microRNAs, proteins, and metabolites, are intensively involved in the recovery and repair processes of joint injuries. Thus, a comprehensive understanding of their roles and mechanisms is essential for devising innovative therapeutic strategies and improving patient outcomes. This review seeks to elucidate the function of extracellular vesicles in synovial membrane injuries associated with sports and their potential clinical applications, aiming to advance therapeutic approaches and enhance the management of joint diseases.
Article Details
Copyright (c) 2025 Yan L, et al.
This work is licensed under a Creative Commons Attribution 4.0 International License.
1. Olivotto E, Belluzzi E, Pozzuoli A, Cigolotti A, Scioni M, Goldring SR, et al. Do synovial inflammation and meniscal degeneration impact clinical outcomes of patients undergoing arthroscopic partial meniscectomy? A histological study. Int J Mol Sci. 2022;23(7):3903. Available from: https://www.mdpi.com/1422-0067/23/7/3903
2. Cao M, Ong MTY, Yung PSH, Tuan RS, Jiang Y. Role of synovial lymphatic function in osteoarthritis. Osteoarthritis Cartilage. 2022;30(9):1186-1197. Available from: https://www.sciencedirect.com/science/article/pii/S1063458422001261
3. Lattanzi B, Lanni S, Luniew E, Giangiacomi M, Ravelli A, Jorini M. Ann Rheum Dis. 2015;74(Suppl 2):1221. Available from: https://www.proquest.com/docview/1901803606?sourcetype=Scholarly%20Journals#
4. Pereira DF, Natour J, Buosi AL, Ferreira FB, Fernandes Ada R, Furtado RN. Is painless synovitis different from painful synovitis? A controlled, ultrasound, radiographic, clinical trial. Clinics (Sao Paulo). 2014;69(2):93-100. Available from: https://www.scielo.br/j/clin/a/y4c7vGhHrF6Kd8qTtjBdXYC/?lang=en
5. Motta F, Barone E, Sica A, Selmi C. Inflammaging and osteoarthritis. Clin Rev Allergy Immunol. 2023;64(2):222-238. Available from: https://link.springer.com/article/10.1007/s12016-022-08941-1
6. d'Ailly PN, Deugd C, Schep NWL, Kuijper TM, Kok MR, Willemze A, et al. Arthroscopic synovectomy versus intra-articular injection of corticosteroids for the management of refractory psoriatic or rheumatoid arthritis of the wrist: study protocol for a randomized controlled trial (ARCTIC trial). Trials. 2023;24(1):229. Available from: https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07129-y
7. Ferguson LD, Siebert S, McInnes IB, Sattar N. Cardiometabolic comorbidities in RA and PsA: lessons learned and future directions. Nat Rev Rheumatol. 2019;15(8):461-474. Available from: https://www.nature.com/articles/s41584-019-0256-0
8. Hohmann E. Editorial commentary: more clinical trials should focus on primary prevention of osteoarthritis: disruptive thinkers are required. Arthroscopy. 2021;37(8):2640-2641. Available from: https://www.arthroscopyjournal.org/article/S0749-8063(21)00586-3/fulltext
9. Luft FC. Osteoarthritis is what the people have. J Mol Med. 2015;93:819–821. Available from: https://link.springer.com/article/10.1007/s00109-015-1316-9
10. Ben-Trad L, Matei CI, Sava MM, Filali S, Duclos ME, Berthier Y, et al. Synovial extracellular vesicles: structure and role in synovial fluid tribological performances. Int J Mol Sci. 2022;23:11998. Available from: https://www.mdpi.com/1422-0067/23/19/11998
11. Leidal AM, Debnath J. Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles. Methods. 2020;177:15-26. Available from: https://www.sciencedirect.com/science/article/pii/S1046202320300213
12. Harrell CR, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells. 2019;8(12):1605. Available from: https://www.mdpi.com/2073-4409/8/12/1605
13. Pan C, Huang W, Chen Q, Xu J, Yao G, Li B, et al. LncRNA Malat-1 from MSCs-derived extracellular vesicles suppresses inflammation and cartilage degradation in osteoarthritis. Front Bioeng Biotechnol. 2021;9:772002. Available from: https://www.frontiersin.org/articles/10.3389/fbioe.2021.772002/full
14. Wu R, Fan X, Wang Y, Shen M, Zheng Y, Zhao S, et al. Mesenchymal stem cell-derived extracellular vesicles in liver immunity and therapy. Front Immunol. 2022;13:833878. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2022.833878/full
15. Alcaraz MJ. Control of articular degeneration by extracellular vesicles from stem/stromal cells as a potential strategy for the treatment of osteoarthritis. Biochem Pharmacol. 2024;228:116226. Available from: https://www.sciencedirect.com/science/article/pii/S0006295224001407
16. van Niel G, Carter DRF, Clayton A, Lambert DW, Raposo G, Vader P. Challenges and directions in studying cell-cell communication by extracellular vesicles. Nat Rev Mol Cell Biol. 2022;23(5):369-382. Available from: https://www.nature.com/articles/s41580-022-00460-3
17. Pathan M, Fonseka P, Chitti SV, Kang T, Sanwlani R, Van Deun J, et al. Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res. 2019;47(D1):D516-D519. Available from: https://academic.oup.com/nar/article/47/D1/D516/5146197
18. Zhang W, Huang P, Lin J, Zeng H. The role of extracellular vesicles in osteoporosis: a scoping review. Membranes (Basel). 2022;12(3):324. Available from: https://www.mdpi.com/2077-0375/12/3/324
19. Park SH, Lee EK, Yim J, Lee MH, Lee E, Lee YS, et al. Exosomes: nomenclature, isolation, and biological roles in liver diseases. Biomol Ther (Seoul). 2023;31:253-263. Available from: https://www.biomolther.org/journal/view.html?volume=31&number=3&spage=253
20. Amin S, Massoumi H, Tewari D, Roy A, Chaudhuri M, Jazayerli C, et al. Cell type-specific extracellular vesicles and their impact on health and disease. Int J Mol Sci. 2024;25:2730. Available from: https://www.mdpi.com/1422-0067/25/5/2730
21. Chen J, Yu X, Zhang X. Advances on biological functions of exosomal non-coding RNAs in osteoarthritis. Cell Biochem Funct. 2022;40:49–59. Available from: https://onlinelibrary.wiley.com/doi/10.1002/cbf.3679
22. Du S, Ling H, Guo Z, Cao Q, Song C. Roles of exosomal miRNA in vascular aging. Pharmacol Res. 2021;165:105278. Available from: https://www.sciencedirect.com/science/article/pii/S1043661820303654
23. Logvina NA, Shender VO, Arapidi GP, Holina TD. A role of vesicular transduction of intercellular signals in cancer development. Russ J Bioorg Chem. 2018;44:129–139. Available from: https://link.springer.com/article/10.1134/S1068162018010120
24. Mittal S, Gupta P, Chaluvally-Raghavan P, Pradeep S. Emerging role of extracellular vesicles in immune regulation and cancer progression. Cancers (Basel). 2020;12:3563. Available from: https://www.mdpi.com/2072-6694/12/12/3563
25. Zhou Z, Tao Y, Zhao H, Wang Q. Adipose extracellular vesicles: messengers from and to macrophages in regulating immunometabolic homeostasis or disorders. Front Immunol. 2021;12:666344. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2021.666344/full
26. Kyung Chang S, Gu Z, Brenner MB. Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. Immunol Rev. 2010;233:256–266. Available from: https://onlinelibrary.wiley.com/doi/10.1111/j.0105-2896.2009.00854.x
27. Li N, Gao J, Mi L, Zhang G, Zhang L, Zhang N, et al. Synovial membrane mesenchymal stem cells: past life, current situation, and application in bone and joint diseases. Stem Cell Res Ther. 2020;11:381. Available from: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-020-01885-3
28. Køster D, Egedal JH, Lomholt S, Hvid M, Jakobsen MR, Müller-Ladner U, et al. Phenotypic and functional characterization of synovial fluid-derived fibroblast-like synoviocytes in rheumatoid arthritis. Sci Rep. 2021;11:22168. Available from: https://www.nature.com/articles/s41598-021-01692-7
29. Levick JR, McDonald JN. Fluid movement across synovium in healthy joints: role of synovial fluid macromolecules. Ann Rheum Dis. 1995;54:417–423. Available from: https://ard.bmj.com/content/54/5/417
30. Jimenez SA, Derk CT. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann Intern Med. 2004;140:37. Available from: https://pubmed.ncbi.nlm.nih.gov/14706971/
31. Hudalla GA. Medical applications of glycomaterials. Adv Healthc Mater. 2022;11:2200096. Available from: https://onlinelibrary.wiley.com/doi/10.1002/adhm.202200096
32. Sadique M, Shah SR, Sharma SK, Islam SMN. Effect of significant parameters on squeeze film characteristics in pathological synovial joints. Mathematics. 2023;11:1468. Available from: https://www.mdpi.com/2227-7390/11/6/1468
33. Liu Q, Zhang Y. Biological clock perspective in rheumatoid arthritis. Inflammation. 2025;48(3):1028–1041. Available from: https://link.springer.com/article/10.1007/s10753-024-02120-4
34. Neumann E, Junker S, Schett G, Frommer K, Müller-Ladner U. Adipokines in bone disease. Nat Rev Rheumatol. 2016;12:296–302. Available from: https://www.nature.com/articles/nrrheum.2016.49
35. Al-Madol MA, Shaqura M, John T, Likar R, Ebied RS, Salih MM, et al. Prostanoid receptor subtypes and its endogenous ligands with processing enzymes within various types of inflammatory joint diseases. Mediators Inflamm. 2020;2020:4301072. Available from: https://www.hindawi.com/journals/mi/2020/4301072/
36. Philpott HT, Birmingham TB, Fiset B, Walsh LA, Coleman MC, Séguin CA, et al. Tensile strain and altered synovial tissue metabolism in human knee osteoarthritis. Sci Rep. 2022;12:17367. Available from: https://www.nature.com/articles/s41598-022-22459-8
37. Hardy J, Bertone AL, Muir WW. Local hemodynamics, permeability, and oxygen metabolism during acute inflammation of innervated or denervated isolated equine joints. Am J Vet Res. 1998;59:1307. Available from: https://pubmed.ncbi.nlm.nih.gov/9781467/
38. Pérez-García S, Carrión M, Gutiérrez-Cañas I, Villanueva-Romero R, Castro D, Martínez C, et al. Profile of matrix-remodeling proteinases in osteoarthritis: impact of fibronectin. Cells. 2019;9:40. Available from: https://www.mdpi.com/2073-4409/9/1/40
39. Tamai K, Hamada J, Nagase Y, Morishige M, Naito M, Asai H, et al. Frozen shoulder. An overview of pathology and biology with hopes to novel drug therapies. Mod Rheumatol. 2024;34:439–443. Available from: https://academic.oup.com/mr/article/34/3/439/7663085
40. Liu F, Lu Y, Wang X, Sun S, Pan H, Wang M, et al. Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling. Protein Cell. 2024;15:441–459. Available from: https://academic.oup.com/protein-cell/article/15/5/441/7670122
41. Wei Q, Zhu X, Wang L, Zhang W, Yang X, Wei W. Extracellular matrix in synovium development, homeostasis and arthritis disease. Int Immunopharmacol. 2023;121:110453. Available from: https://www.sciencedirect.com/science/article/pii/S1567576923002296
42. Sanchez-Lopez E, Coras R, Torres A, Lane NE, Guma M. Synovial inflammation in osteoarthritis progression. Nat Rev Rheumatol. 2022;18:258–275. Available from: https://www.nature.com/articles/s41584-022-00749-9
43. Zhao Y, Li X, Zhang W, Yu L, Wang Y, Deng Z, et al. Trends in the biological functions and medical applications of extracellular vesicles and analogues. Acta Pharm Sin B. 2021;11:2114–2135. Available from: https://www.sciencedirect.com/science/article/pii/S2211383521000594
44. Malda J, Boere J, Van De Lest CHA, Van Weeren PR, Wauben MHM. Extracellular vesicles—new tool for joint repair and regeneration. Nat Rev Rheumatol. 2016;12:243–249. Available from: https://www.nature.com/articles/nrrheum.2015.170
45. Horváth E, Sólyom Á, Székely J, Nagy EE, Popoviciu H. Inflammatory and metabolic signaling interfaces of the hypertrophic and senescent chondrocyte phenotypes associated with osteoarthritis. Int J Mol Sci. 2023;24:16468. Available from: https://www.mdpi.com/1422-0067/24/22/16468
46. Tang Z, Feng H, Chen X, Shao S, Li C. SNORC knockdown alleviates inflammation, autophagy defect and matrix degradation of chondrocytes in osteoarthritis development. Mol Cell Biochem. 2023. Available from: https://link.springer.com/article/10.1007/s11010-023-04842-9
47. Denkovskij J, Bagdonas E, Kusleviciute I, Mackiewicz Z, Unguryte A, Porvaneckas N, et al. Paracrine potential of the human adipose tissue-derived stem cells to modulate balance between matrix metalloproteinases and their inhibitors in the osteoarthritic cartilage in vitro. Stem Cells Int. 2017;2017:9542702. Available from: https://www.hindawi.com/journals/sci/2017/9542702/
48. Kato T, Miyaki S, Ishitobi H, Nakamura Y, Nakasa T, Lotz MK, et al. Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Res Ther. 2014;16:R163. Available from: https://arthritis-research.biomedcentral.com/articles/10.1186/ar4679
49. Kovács B, Vajda E, Nagy EE. Regulatory effects and interactions of the Wnt and OPG-RANKL-RANK signaling at the bone-cartilage interface in osteoarthritis. Int J Mol Sci. 2019;20:4653. Available from: https://www.mdpi.com/1422-0067/20/18/4653
50. Łęgosz P, Sarzyńska S, Pulik Ł, Kotrych D, Małdyk P. The complexity of molecular processes in osteoarthritis of the knee joint. Open Med (Wars). 2020;15:366–375. Available from: https://www.degruyter.com/document/doi/10.1515/med-2020-0402/html
51. Gao K, Zhu W, Li H, Ma D, Liu W, Yu W, et al. Association between cytokines and exosomes in synovial fluid of individuals with knee osteoarthritis. Mod Rheumatol. 2020;30:758–764. Available from: https://www.tandfonline.com/doi/full/10.1080/14397595.2019.1651445
52. Liu B, Xian Y, Chen X, Shi Y, Dong J, Yang L, et al. Inflammatory fibroblast-like synoviocyte-derived exosomes aggravate osteoarthritis via enhancing macrophage glycolysis. Adv Sci (Weinh). 2024;11:2307338. Available from: https://onlinelibrary.wiley.com/doi/10.1002/advs.202307338
53. Ni Z, Kuang L, Chen H, Xie Y, Zhang B, Ouyang J, et al. The exosome-like vesicles from osteoarthritic chondrocytes enhanced mature IL-1β production of macrophages and aggravated synovitis in osteoarthritis. Cell Death Dis. 2019;10:522. Available from: https://www.nature.com/articles/s41419-019-1739-2
54. Liu G, Kang G, Wang S, Huang Y, Cai Q. Extracellular vesicles: emerging players in plant defense against pathogens. Front Plant Sci. 2021;12:757925. Available from: https://www.frontiersin.org/articles/10.3389/fpls.2021.757925/full
55. Sun W, Cui H, Xu T, Yue J, Liang J, You W, et al. RNA binding proteins in extracellular vesicles and their potential value for cancer diagnosis and treatment (Review). Int J Oncol. 2023;63:114. Available from: https://www.spandidos-publications.com/10.3892/ijo.2023.5562
56. Cheng WJ, Yang HT, Chiang CC, Lai KH, Chen YL, Shih HL, et al. Deer velvet antler extracts exert anti-inflammatory and anti-arthritic effects on human rheumatoid arthritis fibroblast-like synoviocytes and distinct mouse arthritis. Am J Chin Med. 2022;50:1617–1643. Available from: https://www.worldscientific.com/doi/10.1142/S0192415X22500689
57. Bai Z, Bartelo N, Aslam M, Murphy EA, Hale CR, Blachere NE, et al. Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis. Sci Transl Med. 2024;16:eadk3506. Available from: https://www.science.org/doi/10.1126/scitranslmed.adk3506
58. Wang J, Sun T. Mir-25-3p in extracellular vesicles from fibroblast-like synoviocytes alleviates pyroptosis of chondrocytes in knee osteoarthritis. J Bioenerg Biomembr. 2023;55:365–380. Available from: https://link.springer.com/article/10.1007/s10863-023-09964-9
59. Xia ZB, Meng FR, Fang YX, Wu X, Zhang CW, Liu Y, et al. Inhibition of NF-κB signaling pathway induces apoptosis and suppresses proliferation and angiogenesis of human fibroblast-like synovial cells in rheumatoid arthritis. Medicine (Baltimore). 2018;97:e10920. Available from: https://journals.lww.com/md-journal/Fulltext/2018/06150/Inhibition_of_NF_B_signaling_pathway_induces.18.aspx
60. Zhang H, Cai D, Bai X. Macrophages regulate the progression of osteoarthritis. Osteoarthritis Cartilage. 2020;28:555–561. Available from: https://www.sciencedirect.com/science/article/pii/S1063458420300539
61. Zhang J, Rong Y, Luo C, Cui W. Bone marrow mesenchymal stem cell-derived exosomes prevent osteoarthritis by regulating synovial macrophage polarization. Aging (Albany NY). 2020;12:25138–25152. Available from: https://www.aging-us.com/article/104110/text
62. Kim H, Back JH, Han G, Lee SJ, Park YE, Gu MB, et al. Extracellular vesicle-guided in situ reprogramming of synovial macrophages for the treatment of rheumatoid arthritis. Biomaterials. 2022;286:121578. Available from: https://www.sciencedirect.com/science/article/pii/S0142961222003306
63. You B, Zhou C, Yang Y. MSC-EVs alleviate osteoarthritis by regulating microenvironmental cells in the articular cavity and maintaining cartilage matrix homeostasis. Ageing Res Rev. 2023;85:101864. Available from: https://www.sciencedirect.com/science/article/pii/S1568163723001070
64. Wang L, He C. Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front Immunol. 2022;13:967193. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2022.967193/full
65. Ding Y, Chen Q. Recent advances on signaling pathways and their inhibitors in spinal cord injury. Biomed Pharmacother. 2024;176:116938. Available from: https://www.sciencedirect.com/science/article/pii/S0753332224002043
66. Chen P, Zhou J, Ruan A, Guan H, Xie J, Zeng L, et al. Synovial tissue-derived extracellular vesicles induce chondrocyte inflammation and degradation via NF-κB signalling pathway: an in vitro study. J Cell Mol Med. 2022;26(4):2038–2048. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.17227
67. Ren C, Jin J, Hu W, Chen Q, Yang J, Wu Y, et al. Betulin alleviates the inflammatory response in mouse chondrocytes and ameliorates osteoarthritis via AKT/Nrf2/HO-1/NF-κB axis. Front Pharmacol. 2021;12:754038. Available from: https://www.frontiersin.org/articles/10.3389/fphar.2021.754038/full
68. Miao Y, Wu S, Gong Z, Chen Y, Xue F, Liu K, et al. SPARCL1 promotes chondrocytes extracellular matrix degradation and inflammation in osteoarthritis via TNF/NF-κB pathway. J Orthop Transl. 2024;46:116–128. Available from: https://www.sciencedirect.com/science/article/pii/S2214031X24000168
69. Fan W, Xu Z, Liang S, Zuo S, Bian C, Gao X, et al. MLL3 inhibits apoptosis of rheumatoid arthritis fibroblast-like synoviocytes promote secretion of inflammatory factors by activating CCL2 and the NF-κB pathway. Inflammation. 2021;44(5):1803–1814. Available from: https://link.springer.com/article/10.1007/s10753-021-01459-2
70. Cao C, Wu F, Niu X, Hu X, Cheng J, Zhang Y, et al. Cadherin-11 cooperates with inflammatory factors to promote the migration and invasion of fibroblast-like synoviocytes in pigmented villonodular synovitis. Theranostics. 2020;10(24):10573–10588. Available from: https://www.thno.org/v10p10573.htm
71. Wei K, Korsunsky I, Marshall JL, Gao A, Watts GFM, Major T, et al. Notch signalling drives synovial fibroblast identity and arthritis pathology. Nature. 2020;582(7811):259–264. Available from: https://www.nature.com/articles/s41586-020-2222-z
72. Lan T, Luo M, Wei X. Mesenchymal stem/stromal cells in cancer therapy. J Hematol Oncol. 2021;14:195. Available from: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-021-01208-w
73. Hu LW, Wang X, Jiang XQ, Xu LQ, Pan HY. In vivo and in vitro study of osteogenic potency of endothelin-1 on bone marrow-derived mesenchymal stem cells. Exp Cell Res. 2017;357(1):25–32. Available from: https://www.sciencedirect.com/science/article/pii/S0014482717301393
74. Deng J, Wang X, Zhang W, Sun L, Han X, Tong X, et al. Versatile hypoxic extracellular vesicles laden in an injectable and bioactive hydrogel for accelerated bone regeneration. Adv Funct Mater. 2023;33(14):2211664. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/adfm.202211664
75. Liu S, Cao C, Zhang Y, Liu G, Ren W, Ye Y, et al. PI3K/Akt inhibitor partly decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis. J Orthop Surg Res. 2019;14:425. Available from: https://josr-online.biomedcentral.com/articles/10.1186/s13018-019-1394-4
76. Wen M, Li Y, Qin X, Qin B, Wang Q. Insight into cancer immunity: MHCs, immune cells and commensal microbiota. Cells. 2023;12(14):1882. Available from: https://www.mdpi.com/2073-4409/12/14/1882
77. Hu XX, Wu Y, Zhang J, Wei W. T-cells interact with B cells, dendritic cells, and fibroblast-like synoviocytes as hub-like key cells in rheumatoid arthritis. Int Immunopharmacol. 2019;70:428–434. Available from: https://www.sciencedirect.com/science/article/pii/S1567576918324007
78. Sanchez C, Zappia J, Dierckxsens Y, Delcour JP, Henrotin Y. Boswellia serrata extract and curcumin increases GDF15 production by human primary osteoarthritis chondrocytes: a new mechanism of action. Osteoarthritis Cartilage. 2020;28(S1):S120. Available from: https://www.oarsijournal.com/article/S1063-4584(20)30263-6/fulltext
79. Shimoda M. Extracellular vesicle-associated MMPs: a modulator of the tissue microenvironment. In: Makowski GS, editor. Adv Clin Chem. Vol. 88. Amsterdam: Elsevier; 2019;35–66. Available from: https://www.sciencedirect.com/science/article/abs/pii/S006524231830046X
80. Thuault S, Ghossoub R, David G, Zimmermann P. A journey on extracellular vesicles for matrix metalloproteinases: a mechanistic perspective. Front Cell Dev Biol. 2022;10:886381. Available from: https://www.frontiersin.org/articles/10.3389/fcell.2022.886381/full
81. Lättekivi F, Guljavina I, Midekessa G, Viil J, Heath PR, Bæk R, et al. Profiling blood serum extracellular vesicles in plaque psoriasis and psoriatic arthritis patients reveals potential disease biomarkers. Int J Mol Sci. 2022;23(7):4005. Available from: https://www.mdpi.com/1422-0067/23/7/4005
82. Poulsen TBG, Andersen JS, Kristiansen MK, Rasmusen S, Arent-Nielsen L, Nielsen CH, et al. AB1254 phenotyping of multiple biofluids for liquid biomarkers for diagnostics and personalized medicine of rheumatoid arthritis, spondyloarthritis and osteoarthritis. Ann Rheum Dis. 2020;79(Suppl 1):1918–1919. Available from: https://ard.bmj.com/content/79/Suppl_1/1918.2
83. Gong J, Zhang X, Khan A, Liang J, Xiong T, Yang P, et al. Identification of serum exosomal miRNA biomarkers for diagnosis of rheumatoid arthritis. Int Immunopharmacol. 2024;129:111604. Available from: https://www.sciencedirect.com/science/article/pii/S1567576924000834
84. Maeda Y, Farina NH, Matzelle MM, Fanning PJ, Lian JB, Gravallese EM. Synovium-derived microRNAs regulate bone pathways in rheumatoid arthritis. J Bone Miner Res. 2017;32(3):461–472. Available from: https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3005
85. Kolhe R, Hunter M, Liu S, Jadeja RN, Pundkar C, Mondal AK, et al. Gender-specific differential expression of exosomal miRNA in synovial fluid of patients with osteoarthritis. Sci Rep. 2017;7:2029. Available from: https://www.nature.com/articles/s41598-017-01905-y
86. Ortega A, Martinez-Arroyo O, Forner MJ, Cortes R. Exosomes as drug delivery systems: endogenous nanovehicles for treatment of systemic lupus erythematosus. Pharmaceutics. 2020;13(1):3. Available from: https://www.mdpi.com/1999-4923/13/1/3
87. Ansboro S, Roelofs AJ, De Bari C. Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both? Curr Opin Rheumatol. 2017;29(2):201–207. Available from: https://doi.org/10.1097/bor.0000000000000370
88. Li S, Liu J, Liu S, Jiao W, Wang X. Chitosan oligosaccharides packaged into rat adipose mesenchymal stem cells-derived extracellular vesicles facilitating cartilage injury repair and alleviating osteoarthritis. J Nanobiotechnol. 2021;19:343. Available from: https://doi.org/10.1186/s12951-021-01086-x
89. Liu W, Liu A, Li X, Sun Z, Sun Z, Liu Y, et al. Dual-engineered cartilage-targeting extracellular vesicles derived from mesenchymal stem cells enhance osteoarthritis treatment via miR-223/NLRP3/pyroptosis axis: toward a precision therapy. Bioact Mater. 2023;30:169–183. Available from: https://doi.org/10.1016/j.bioactmat.2023.06.012
90. Zhou X, Cao H, Guo J, Yuan Y, Ni G. Effects of BMSC-derived EVs on bone metabolism. Pharmaceutics. 2022;14(5):1012. Available from: https://doi.org/10.3390/pharmaceutics14051012
91. Zhang J, Rong Y, Luo C, Cui W. Bone marrow mesenchymal stem cell-derived exosomes prevent osteoarthritis by regulating synovial macrophage polarization. Aging. 2020;12(24):25138–25152. Available from: https://doi.org/10.18632/aging.104110
92. Meng Q, Qiu B. Exosomal microRNA-320a derived from mesenchymal stem cells regulates rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing CXCL9 expression. Front Physiol. 2020;11:441. Available from: https://doi.org/10.3389/fphys.2020.00441
93. Li JK, Yang C, Su Y, Luo JC, Luo MH, Huang DL, et al. Mesenchymal stem cell-derived extracellular vesicles: a potential therapeutic strategy for acute kidney injury. Front Immunol. 2021;12:684496. Available from: https://doi.org/10.3389/fimmu.2021.684496
94. You DG, Oh BH, Nguyen VQ, Lim GT, Um W, Jung JM, et al. Vitamin A-coupled stem cell-derived extracellular vesicles regulate the fibrotic cascade by targeting activated hepatic stellate cells in vivo. J Control Release. 2021;336:285–295. Available from: https://doi.org/10.1016/j.jconrel.2021.06.031
95. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977. Available from: https://doi.org/10.1126/science.aau6977
96. Lu Y, Yang Y, Liu S, Ge S. Biomaterials constructed for MSC-derived extracellular vesicle loading and delivery—a promising method for tissue regeneration. Front Cell Dev Biol. 2022;10:898394. Available from: https://doi.org/10.3389/fcell.2022.898394
97. Dong Y, Xia P, Xu X, Shen J, Ding Y, Jiang Y, et al. Targeted delivery of organic small-molecule photothermal materials with engineered extracellular vesicles for imaging-guided tumor photothermal therapy. J Nanobiotechnol. 2023;21:442. Available from: https://doi.org/10.1186/s12951-023-02133-5
98. Liu H, Wu Y, Wang F, Wang S, Ji N, Wang M, et al. Bone-targeted engineered bacterial extracellular vesicles delivering miRNA to treat osteoporosis. Compos Part B Eng. 2023;267:111047. Available from: https://doi.org/10.1016/j.compositesb.2023.111047
99. Zhang H, Yan W, Wang J, Xie S, Tao WA, Lee CW, et al. Surface functionalization of exosomes for chondrocyte-targeted siRNA delivery and cartilage regeneration. J Control Release. 2024;369:493–505. Available from: https://doi.org/10.1016/j.jconrel.2024.04.009
100. Wu Y, Li X, Wang Y, Shi Y, Wang F, Lin G. Research progress on mechanical properties and wear resistance of cartilage repair hydrogel. Mater Des. 2022;216:110575. Available from: https://doi.org/10.1016/j.matdes.2022.110575
101. Wang L, Wei X, He X, Xiao S, Shi Q, Chen P, et al. Osteoinductive dental pulp stem cell-derived extracellular vesicle-loaded multifunctional hydrogel for bone regeneration. ACS Nano. 2024;18(7):8777–8797. Available from: https://doi.org/10.1021/acsnano.3c11542
102. Wu D, Qin H, Wang Z, Yu M, Liu Z, Peng H, et al. Bone mesenchymal stem cell-derived sEV-encapsulated thermosensitive hydrogels accelerate osteogenesis and angiogenesis by release of exosomal miR-21. Front Bioeng Biotechnol. 2022;9:829136. Available from: https://doi.org/10.3389/fbioe.2021.829136
103. Yang S, Zhu B, Yin P, Zhao L, Wang Y, Fu Z, et al. Integration of human umbilical cord mesenchymal stem cells-derived exosomes with hydroxyapatite-embedded hyaluronic acid-alginate hydrogel for bone regeneration. ACS Biomater Sci Eng. 2020;6(3):1590–1602. Available from: https://doi.org/10.1021/acsbiomaterials.9b01363
104. Li S, Zheng W, Deng W, Li Z, Yang J, Zhang H, et al. Logic-based strategy for spatiotemporal release of dual extracellular vesicles in osteoarthritis treatment. Adv Sci. 2024;11:2403227. Available from: https://doi.org/10.1002/advs.202403227
105. Cecchin R, Troyer Z, Witwer K, Morris KV. Extracellular vesicles: the next generation in gene therapy delivery. Mol Ther. 2023;31(5):1225–1230. Available from: https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(23)00021-7
106. Carr HL, Turner JD, Major T, Scheel-Toellner D, Filer A. New developments in transcriptomic analysis of synovial tissue. Front Med. 2020;7:21. Available from: https://doi.org/10.3389/fmed.2020.00021
107. Chen D, Yu H, Zhang Y, Huang Y. Metabolomic analysis of extracellular vesicles from human synovial fluids. Microchem J. 2022;177:107257. Available from: https://doi.org/10.1016/j.microc.2022.107257
108. Yang B, Li X, Fu C, Cai W, Meng B, Qu Y, et al. Extracellular vesicles in osteoarthritis of peripheral joint and temporomandibular joint. Front Endocrinol. 2023;14:1158744. Available from: https://doi.org/10.3389/fendo.2023.1158744
109. Qian K, Fu W, Li T, Zhao J, Lei C, Hu S. The roles of small extracellular vesicles in cancer and immune regulation and translational potential in cancer therapy. J Exp Clin Cancer Res. 2022;41:286. Available from: https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02492-1
110. Wang C, Xu M, Fan Q, Li C, Zhou X. Therapeutic potential of exosome-based personalized delivery platform in chronic inflammatory diseases. Asian J Pharm Sci. 2023;18:100772. Available from: https://doi.org/10.1016/j.ajps.2022.100772
111. Liu XC, Zhang HJ, Xu R, Liu J, Xia HF, Xie QH, et al. A NIR-II quantum dot-assisted dual-color imaging strategy enables simultaneous tracking of two subtypes of extracellular vesicles in vivo. Chem Eng J. 2024;492:152242. Available from: https://doi.org/10.1016/j.cej.2024.152242
112. Mohammadipoor A, Hershfield MR, Linsenbardt HR, Smith J, Mack J, Natesan S, et al. Biological function of extracellular vesicles (EVs): a review of the field. Mol Biol Rep. 2023;50(22):8639–8651. Available from: https://doi.org/10.1007/s11033-023-08624-w
113. Zhang C, Yang X, Jiang T, Yan C, Xu X, Chen Z. Tissue-derived extracellular vesicles: isolation, purification, and multiple roles in normal and tumor tissues. Life Sci. 2023;321:121624. Available from: https://doi.org/10.1016/j.lfs.2023.121624
114. Nguyen J, Fuhrmann G. Extracellular vesicles — a versatile biomaterial. Adv Healthc Mater. 2022;11:e2200192. Available from: https://doi.org/10.1002/adhm.202200192
115. Frampton AE, Giovannetti E. Diagnosing pancreatic ductal adenocarcinoma using plasma extracellular vesicle RNA profiles. Gut. 2020;69(3):404–405. Available from: https://doi.org/10.1136/gutjnl-2019-319896