Engineered M2 macrophage-derived extracellular vesicles reprogram mitochondrial metabolism to alleviate...

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative joint disease characterized by progressive degradation of the cartilage matrix. Current clinical interventions mainly offer symptomatic relief but fail to halt disease progression. The pathogenesis of TMJOA is driven by mitochondrial dysfunction, which promotes both chondrocyte inflammation and extracellular matrix breakdown. To address these issues, an integrated therapeutic system was developed by encapsulating curcumin into M2 macrophage-derived extracellular vesicles (Cur@M2-EVs) through ultrasonic processing. In vitro studies demonstrated that Cur@M2-EVs effectively attenuated inflammatory responses and cartilage matrix degradation by scavenging reactive oxygen species (ROS), restoring mitochondrial membrane potential, and shifting cellular metabolism from glycolysis back to oxidative phosphorylation. Furthermore, transcriptomic analysis and experimental validation revealed that Cur@M2-EVs alleviate chondrocyte inflammation primarily by suppressing Thbs1 expression. To enable sustained drug release and enhance joint lubrication, Cur@M2-EVs were further encapsulated within poly (ethylene glycol) diacrylate (PEGDA) hydrogel microspheres, forming the Cur@M2-EVs@PEGDA system. In a monosodium iodoacetate (MIA)-induced rat model of TMJOA, intra-articular injection of Cur@M2-EVs@PEGDA microspheres significantly alleviated cartilage destruction and improved joint lubrication. This study proposes a novel disease-modifying strategy for TMJOA treatment by integrating mitochondrial regulation, immunomodulation, and sustained lubricating release within a single platform, offering a promising therapeutic approach for this challenging condition.