Bimetallic Copper–Manganese Zeolitic Imidazolate Framework Nanozyme Scavenges Reactive Oxygen Species to Alleviate Osteoarthritis via Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Axis and Autophagic Flux Restoration

Osteoarthritis (OA) is the fastest-growing cause of physical disability worldwide, yet no therapy currently halts its age-dependent progression. Increasing evidence suggests that reactive oxygen species (ROS) are central drivers of cartilage degradation and OA progression. Therefore, the clearance of ROS is critical for mitigating OA progression and developing effective therapeutic strategies. In this study, we report a bioinspired copper-manganese zeolitic imidazolate framework (CuMn-ZIF) that integrates catalase (CAT) and superoxide dismutase (SOD)-mimetic activities within a single nanoplatform. By simultaneously scavenging H₂O₂ and superoxide anions, the CuMn-ZIF nanozyme rebalances redox status in human OA chondrocytes, suppressing PI3K-AKT-mTOR signaling and restoring lysosomal-autophagic flux. An intra-articular injection in destabilized medial meniscus (DMM) mice markedly ameliorated cartilage deterioration and subchondral bone loss, showing a 1.5-fold increase in bone mineral density (BMD), a 2.1-fold greater bone volume/tissue volume (BV/TV), and a 2-fold increase in trabecular number compared to DMM controls. Comprehensive in vitro and in vivo analyses validated the CuMn-ZIF nanozyme as a potent therapeutic agent, demonstrating exceptional catalytic activity and reproducible disease-modifying effects in OA. This work establishes a scalable blueprint for ROS-targeting, enzyme-mimetic nanomedicines that can potentially be translated to treat OA and other ROS-dependent diseases.