Reprogramming Macrophage Polarization, Depleting ROS by Astaxanthin and Thioketal‐Containing Polymers Delivering Rapamycin for Osteoarthritis Treatment

Abstract Osteoarthritis (OA) is a chronic joint disease characterized by synovitis and joint cartilage destruction. The severity of OA is highly associated with the imbalance between M1 and M2 synovial macrophages. In this study, a novel strategy is designed to modulate macrophage polarization by reducing intracellular reactive oxygen species (ROS) levels and regulating mitochondrial function. A ROS‐responsive polymer is synthesized to self‐assemble with astaxanthin and autophagy activator rapamycin to form nanoparticles (NP@Poly RHAPM ). In vitro experiments show that NP@Poly RHAPM significantly reduced intracellular ROS levels. Furthermore, NP@Poly RHAPM restored mitochondrial membrane potential, increased glutathione (GSH) levels, and promoted intracellular autophagy, hence successfully repolarizing M1 macrophages into the M2 phenotype. This repolarization enhanced chondrocyte proliferation and vitality while inhibiting apoptosis. In vivo experiments utilizing an anterior cruciate ligament transection (ACLT)‐induced OA mouse model revealed the anti‐inflammatory and cartilage‐protective effects of NP@Poly RHAPM , effectively mitigating OA progression. Consequently, the findings suggest that intra‐articular delivery of ROS‐responsive nanocarrier systems holds significant promise as a potential and effective therapeutic strategy for OA treatment.