Microfluidic Methacrylated Hyaluronic Acid Microspheres Incorporating MnO2 and Exosomes for Antioxidant Defense and Inflammation Regulation in Osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degeneration, chronic inflammation, and oxidative stress-induced mitochondrial dysfunction. Herein, we engineered an integrated therapeutic platform by encapsulating mesenchymal stem cell-derived exosomes (Exo) and manganese dioxide (MnO 2 ) nanozymes into methacrylated hyaluronic acid (HAMA) hydrogel microspheres (HAMA-Exo-MnO 2 ) via microfluidic fabrication. Systematic in vitro and in vivo evaluations assessed the microspheres' anti-inflammatory, antioxidant, and chondrogenic regenerative properties. In vitro experiments demonstrated that HAMAExo-MnO 2 microspheres effectively attenuated OA-like pathological changes in chondrocytes, remodeled the inflammatory microenvironment, and scavenged reactive oxygen species (ROS). In a rat OA model induced by destabilization of the medial meniscus (DMM), intra-articular injection of HAMA-Exo-MnO 2 microspheres ameliorated disease progression, enhanced articular cartilage regeneration, and restored joint function. Transcriptomic sequencing and subsequent validation in cocultured OA chondrocytes revealed significant upregulation of ALDH3A1, which mitigated oxidative stress, activated the NRF2 signaling axis, promoted downstream antioxidant gene expression, and restored mitochondrial electron transport chain activity. In summary, this study highlights that the engineered HAMA hydrogel microspheres provide a sophisticated strategy for OA therapy, integrating immune microenvironment modulation, cartilage regeneration, and antioxidant protection.