MSC-EVs in Cartilage Regeneration and Immunomodulation: Mechanisms and Therapeutic Prospects for Osteoarthritis, Rheumatoid Arthritis and Intervertebral Disc Degeneration.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent a promising cell-free therapeutic strategy for cartilage regeneration and inflammation modulation in degenerative and inflammatory musculoskeletal disorders, including osteoarthritis (OA), rheumatoid arthritis (RA) and intervertebral disc degeneration (IVDD). MSC-EVs enhance cartilage repair by promoting chondrocyte proliferation, migration, survival and extracellular matrix (ECM) synthesis to maintain cartilage homeostasis. In parallel, they exert anti-inflammatory and anti-catabolic effects by suppressing inflammatory cytokines, matrix-degrading enzymes, oxidative stress and inflammasome activation. In OA, MSC-EVs regulate chondrocyte function, ECM remodelling, immune responses and tissue regeneration by modulating multiple signalling pathways, including NF-κB, PI3K/AKT, MAPK, Wnt/β-catenin and YAP signalling. In RA, MSC-EVs orchestrate innate and adaptive immune regulation, metabolic reprogramming and tissue repair pathways. In IVDD, MSC-EVs suppress chronic inflammation, reduce nucleus pulposus cell apoptosis, enhance cell proliferation and promote ECM synthesis, facilitating disc regeneration and functional restoration. Despite their therapeutic potential, several challenges hinder clinical translation. This review summarises current understanding of MSC-EV-mediated mechanisms in OA, RA and IVDD, and proposes strategies to enhance therapeutic efficacy and accelerate clinical application in musculoskeletal regenerative medicine.