Mesenchymal stem cells and extracellular vesicles for knee osteoarthritis: clinical application, mechanism exploration and prospect

Knee osteoarthritis (KOA) is a prevalent degenerative joint disease characterized by progressive articular cartilage degeneration, synovial inflammation, and abnormal subchondral bone remodeling, with no curative treatment currently available. Mesenchymal stem cells (MSCs) and their extracellular vesicles (MSC-EVs) have emerged as promising therapeutic strategies for KOA due to their anti-inflammatory, regenerative, and immunomodulatory properties. Clinical studies demonstrate that intra-articular MSCs injection significantly alleviates pain, improves joint function, and exhibits a favorable safety profile. MSC-EVs show enhanced therapeutic potential owing to their low immunogenicity, high stability, and targeted delivery capabilities. This review systematically examines the therapeutic role of MSCs and MSC-EVs in KOA treatment. Mechanistic studies reveal that MSC-EVs ameliorate joint inflammatory microenvironments by regulating macrophage polarization, inhibiting key inflammatory pathways (NF-κB, MAPK), and suppressing pro-inflammatory cytokine release (IL-1β, TNF-α). Furthermore, MSC-EVs protect extracellular matrix integrity and promote cartilage regeneration by upregulating chondrogenic markers (Sox9, aggrecan, type II collagen) while downregulating matrix-degrading enzymes (MMP-13, ADAMTS5). Additionally, MSC-EVs enhance chondrocyte proliferation and migration while inhibiting apoptosis and senescence, potentially through activation of YAP and JAK/STAT signaling pathways. These multifaceted mechanisms collectively facilitate cartilage repair and regeneration. Advances in engineered EVs technology and novel delivery systems provide strategies to further enhance MSC-EVs efficacy. Engineered EVs modified with chondrocyte-targeting peptides or loaded with therapeutic molecules (drugs, miRNAs, siRNAs) can deliver bioactive compounds to specific sites and precisely regulate chondrocyte function, thereby alleviating KOA symptoms. This review comprehensively examines the clinical efficacy and underlying mechanisms of MSCs and MSC-EVs in KOA treatment, discusses current clinical application challenges, and outlines future research directions for advancing precision therapeutic strategies.