Constructing Dual‐Atomic Fe─Fe Sites Nanozyme for Targeted Osteoarthritis Therapy through Mitigating Oxidative Stress and Cartilage Degeneration

Abstract Osteoarthritis progression is driven by excessive reactive oxygen species (ROS), which causes significant secondary damage to chondrocytes and articular cartilage. Herein, the concept of holding desired dual‐site nanozymes is proposed through developing Fe─Fe dimers on nitrogen‐doped porous carbon (Fe ₂ ‐NCs) to eliminate excessive ROS through the co‐adsorption mechanism of superoxide radical. The Fe ₂ ‐NCs present an enhanced ROS performance, effectively mimicking key antioxidant enzymes. Density functional theory calculations indicate that the synergistic effects of the Fe─Fe dimer can modulate oxygen adsorption configurations and accelerating O─O bond‐cleavage. In vitro and in vivo results show that Fe ₂ ‐NCs effectively mitigate ROS, protecting chondrocytes from oxidative stress‐induced apoptosis. The mitochondrial function can be strengthened over Fe ₂ ‐NCs by inhibiting NOX4 expression, restoring ATP levels, and normalizing COXIV expression. Additionally, Fe ₂ ‐NCs significantly downregulate the pro‐inflammatory mediator COX‐2, inhibit MMP‐13‐mediated cartilage degradation, and slow down the type II collagen (COL2) breakdown through the inhibition of NF‐κB signaling pathway.