Extracellular vesicles originating from induced pluripotent stem cell-derived chondrocytes facilitate the regeneration of osteoarthritic cartilage.

BACKGROUND: Articular cartilage, a highly specialized avascular connective tissue, forms a smooth, load-bearing surface on articulating bone ends to facilitate frictionless joint movement. While cell-derived small extracellular vesicles (sEVs) have emerged as promising therapeutic biomaterials for cartilage regeneration, two major limitations impede their clinical translation: the scarcity of autologous donor cells, and suboptimal functional efficacy of conventional sEVs preparations. METHODS: We established an induced pluripotent stem cell (iPSC)-based approach by differentiating iPSCs into chondrocytes (designated iChondrocytes). After characterizing the derived iChondrocytes, we isolated their secreted sEVs (iChondrocyte-sEVs) and systematically evaluated their therapeutic effects and underlying mechanisms in cartilage regeneration through in vitro and in vivo experiments. RESULTS: Functional assays revealed that iChondrocyte-sEVs significantly enhanced chondrogenic differentiation, stimulated extracellular matrix (ECM) deposition, and maintained chondrocyte homeostasis. In murine osteoarthritis (OA) models, intra-articularly administered iChondrocyte-sEVs efficiently penetrated deep cartilage layers, alleviated OA-associated pathological changes, and restored cartilage microstructure and biomechanical properties to near-normal levels. Furthermore, therapeutic intervention with iChondrocyte-sEVs resulted in significant improvements in joint mobility and motor function in OA-affected mice. Proteomic profiling identified serine racemase (SRR) as a key upregulated protein in iChondrocyte-sEVs. Mechanistic studies suggested that SRR may contribute to cartilage regeneration by suppressing the P38/ERK signaling pathway. CONCLUSIONS: This study highlights the significant therapeutic potential of iChondrocyte-sEVs, demonstrating their ability to promote both structural and functional regeneration of articular cartilage. These findings suggest a promising novel strategy for OA treatment. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study highlights the therapeutic potential of iChondrocyte-sEVs, demonstrating their ability to promote both structural and functional regeneration of articular cartilage. These findings indicate a clinical conversion potential for OA treatment.