Thermosensitive Hydrogel Loaded with Primary Chondrocyte-Derived Exosomes Promotes Cartilage Repair by Regulating Macrophage Polarization in Osteoarthritis

Intra-articular injection is a classic strategy for the treatment of early osteoarthritis (OA). However, the local delivery of traditional therapeutic agents has limited benefits for alleviating OA. Exosomes, an important type of extracellular nanovesicle, show great potential for suppressing cartilage destruction in OA to replace drugs and stem cell-based administration.In this study, we developed a thermosensitive, injectable hydrogel by in situ crosslinking of Pluronic F-127 and hyaluronic acid, which can be used as a slow-release carrier to durably retain primary chondrocyte-derived exosomes at damaged cartilage sites to effectively magnify their reparative effect.It was found that the hydrogel can sustainedly release exosomes, positively regulate chondrocytes on the proliferation, migration and differentiation, as well as efficiently induce polarization of M1 to M2 macrophages. Intra-articular injection of this exosomes-incorporated hydrogel significantly prevented cartilage destruction by promoting cartilage matrix formation. This strategy also displayed a regenerative immune phenotype characterized by a higher infiltration of CD163+ regenerative M2 macrophages over CD86+ M1 macrophages in synovial and chondral tissue, with a concomitant reduction in pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and increase in anti-inflammatory cytokine (IL-10) in synovial fluid.Our results demonstrated that local sustained-release primary chondrocyte-derived exosomes may relieve OA by promoting the phenotypic transformation of macrophages from M1 to M2, which suggesting a great potential for the application in OA.