Unlocking an Efficient SOD‐to‐CAT Catalytic Relay in a MOF Nanozyme via Dopamine‐Driven Interfacial Nanoreconstruction for Osteoarthritis Therapy

ABSTRACT Osteoarthritis (OA) is driven by a vicious cycle of inflammation and reactive oxygen species (ROS). While cobalt‐based metal‐organic framework (MOF) nanozymes are potent catalase (CAT) mimics, their therapeutic efficacy is crippled by an inherently weak superoxide dismutase (SOD)‐like activity that prevents full‐chain ROS scavenging. Here, we resolve this imbalance through an innovative “pre‐embedding/activation” strategy. This approach involves pre‐embedding Zn 2+ into a cobalt‐based framework to create a stable yet activatable precursor. The subsequent dopamine (DA)‐driven “activation” then remodels the latent Zn/Co‐N coordination sites, unlocking an efficient SOD‐to‐CAT catalytic relay by synergistically amplifying the SOD‐like activity for seamless elimination of the entire ROS cascade. This powerful scavenging capability restores mitochondrial function and reprograms macrophages toward an anti‐inflammatory M2 phenotype by inhibiting the ROS‐mediated S100A8/NF‐κB signaling axis and its destructive positive feedback loop. The resulting immunomodulation translates to profound therapeutic outcomes in a rat OA model, where it simultaneously promotes chondrocyte anabolism to achieve significant cartilage repair while suppressing peripheral nerve sensitization to provide sustained pain relief. Our work thus establishes nanoscale interfacial reconstruction as a powerful and rational platform for engineering sophisticated catalytic relays within nanozymes for advanced biomedical applications.