Extracellular vesicles derived from adipose-derived mesenchymal stem/stromal cells prevent synovial inflammation and attenuate cartilage degeneration in rodent osteoarthritis.

Objective: Osteoarthritis (OA) is the most common joint disease in the elderly and a major cause of pain and disability. Recent advances in OA therapy have led to a greater variety of treatment options. Extracellular vesicles (EVs) have recently emerged as a potential therapeutic approach for OA. This study aimed to demonstrate the disease-modifying effects of adipose-derived mesenchymal stem cell-derived EVs (MSC-EVs) on OA. Methods: The anti-inflammatory effects of MSC-EVs were evaluated using RAW264.7 macrophage-like cells stimulated with lipopolysaccharide and human synovial cells stimulated with IL-1β. In vivo, MSC-EVs were administered intra-articularly into knees of rats with monosodium iodoacetate (MIA)-induced OA. Pain thresholds, gait parameters, histological scores, and cytokine levels were assessed. Single-cell RNA sequencing (scRNA-seq) was performed on joint tissues to evaluate cell-specific gene expression and macrophage polarization. Results: In vitro, MSC-EVs reduced the mRNA expression of IL-1β and IL-6 in RAW264.7 cells, and significantly suppressed multiple inflammatory cytokines while upregulating FGF-18 in synovial cells. In vivo, intra-articular MSC-EV injection increased pain threshold, improved gait, and reduced synovial inflammation and cartilage degeneration. scRNA-seq revealed decreased inflammatory cytokines, increased PRG4 and FGF-18 expression, and a shift in macrophage polarization toward an M2 phenotype in the EV-treated group. Conclusion: MSC-EVs exert anti-inflammatory and cartilage-protective effects in OA through immune modulation and regenerative signaling, indicating their significant therapeutic potential as a disease-modifying strategy for OA.