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, we developed a promising strategy to fabricate high-yield exosome-mimicking MSC-derived nanovesicles (MSC-NVs) with enhanced regenerative and anti-inflammatory capabilities. MSC-NVs were prepared using an extrusion approach and were found to increase chondrocyte and human bone marrow MSC differentiation, proliferation, and migration, in addition to inducing M2 macrophage polarization. Furthermore, we formulated gelatin methacryloyl (GelMA) hydrogels loaded with MSC-NVs (GelMA-NVs), which exhibited sustained release of MSC-NVs and were 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 ameliorated osteoarthritis severity, reduced the secretion of catabolic factors, and enhanced matrix synthesis. Furthermore, GelMA-NVs induced M2 macrophage polarization and inflammatory response inhibition in vivo. Our findings demonstrate that GelMA-NVs hold promise for osteoarthritis treatment through modulation of chondrogenesis and macrophage polarization. This article is protected by copyright. All rights reserved.