Treatment with Mesenchymal Stem Cell-Derived Nanovesicle-Containing Gelatin Methacryloyl Hydrogels Alleviates Osteoarthritis by Modulating Chondrogenesis and Macrophage Polarization.

Osteoarthritis is a degenerative disorder that can severely affect joints, and new treatment strategies are urgently needed. Administration of mesenchymal stem cell (MSC)-derived exosomes is a promising therapeutic strategy in osteoarthritis treatment. However, the poor yield of exosomes is an obstacle to the use of this modality in the clinic. Herein, a promising strategy is developed to fabricate high-yield exosome-mimicking MSC-derived nanovesicles (MSC-NVs) with enhanced regenerative and anti-inflammatory capabilities. MSC-NVs are prepared using an extrusion approach and are found to increase chondrocyte and human bone marrow MSC differentiation, proliferation, and migration, in addition to inducing M2 macrophage polarization. Furthermore, gelatin methacryloyl (GelMA) hydrogels loaded with MSC-NVs (GelMA-NVs) are formulated, which exhibit sustained release of MSC-NVs and are shown to be biocompatible with excellent mechanical properties. In a mouse osteoarthritis model constructed by surgical destabilization of the medial meniscus (DMM), GelMA-NVs effectively ameliorate osteoarthritis severity, reduce the secretion of catabolic factors, and enhance matrix synthesis. Furthermore, GelMA-NVs induce M2 macrophage polarization and inflammatory response inhibition in vivo. The findings demonstrate that GelMA-NVs hold promise for osteoarthritis treatment through modulation of chondrogenesis and macrophage polarization.