Trimanganese Tetroxide Nanozyme protects Cartilage against Degeneration by Reducing Oxidative Stress in Osteoarthritis

Abstract Osteoarthritis, a chronic degenerative cartilage disease, is the leading cause of movement disorders among humans. Although the specific pathogenesis and associated mechanisms remain unclear, oxidative stress‐induced metabolic imbalance in chondrocytes plays a crucial role in the occurrence and development of osteoarthritis. In this study, a trimanganese tetroxide (Mn 3 O 4 ) nanozyme with superoxide dismutase (SOD)‐like and catalase (CAT)‐like activities is designed to reduce oxidative stress‐induced damage and its therapeutic effect is investigated. In vitro, Mn 3 O 4 nanozymes are confirmed to reprogram both the imbalance of metabolism in chondrocytes and the uncontrolled inflammatory response stimulated by hydrogen peroxide. In vivo, a cross‐linked chondroitin sulfate (CS) hydrogel is designed as a substrate for Mn 3 O 4 nanozymes to treat osteoarthritis in mouse models. As a result, even in the early stage of OA (4 weeks), the therapeutic effect of the Mn 3 O 4 @CS hydrogel is observed in both cartilage metabolism and inflammation. Moreover, the Mn 3 O 4 @CS hydrogel maintained its therapeutic effects for at least 7 days, thus revealing a broad scope for future clinical applications. In conclusion, these results suggest that the Mn 3 O 4 @CS hydrogel is a potentially effective therapeutic treatment for osteoarthritis, and a novel therapeutic strategy for osteoarthritis based on nanozymes is proposed.