Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles for Immunomodulation in Osteoarthritis

Osteoarthritis (OA) is a heterogeneous disorder affecting multiple joint tissues, in which structural degeneration may be accompanied by varying degrees of synovial inflammation and immune–stromal dysregulation. Mesenchymal stem/stromal cells (MSCs) have demonstrated immunomodulatory and tissue-protective properties, increasingly linked to paracrine signaling. Comparative studies suggest that extracellular vesicles (EVs) make an important, but not exclusive, contribution to MSC paracrine activity, with soluble secretome components providing potentially complementary effects. Drawing on literature identified primarily through PubMed and Scopus and clinical trial records from ClinicalTrials.gov (updated through September 2026), this narrative review examines the immunomodulatory role of MSC-derived EVs (MSC-EVs) in OA, with emphasis on their interactions with the joint immune microenvironment and their contribution to tissue protection. Across experimental OA models, MSC-EVs have been reported to reduce synovitis, cartilage degeneration, subchondral bone alterations, and pain-related outcomes, although responses vary with MSC source, EV composition, engineering strategies, disease context, and treatment regimen. Mechanistically, the most consistent evidence supports modulation of macrophage-associated inflammatory responses, whereas effects on adaptive immune populations remain less established and are largely derived from non-OA models. Clinical evidence remains limited and currently provides mainly preliminary information on feasibility and short-term tolerability, with insufficient evidence to establish therapeutic efficacy. Overall, MSC-EVs represent a potential cell-free immunomodulatory approach for OA, but standardized manufacturing, product characterization, dosing, and rigorously controlled clinical trials are required to define their therapeutic value.