NIR‐Responsive Mitochondrial‐Targeted Nanozymes With Built‐In Antibacterial Function for Safe Osteoarthritis Therapy

Abstract

Osteoarthritis is a prevalent degenerative joint disorder characterized by chronic inflammation and oxidative stress, with current treatments offering limited efficacy in halting disease progression. A central pathogenic driver is the mitochondrial overproduction of reactive oxygen species (ROS), which induces cellular components damage, propagates inflammatory signaling, and accelerates cellular senescence. Although some natural enzymes can neutralize ROS, their therapeutic applications are severely restricted by poor stability and limited cellular uptake. Here, a mitochondrial targeted nanozyme (CuQ@SS31) is fabricated by coordinating copper with quercetin and modifying the mitochondria‐homing peptide SS31 on the surface. CuQ@SS31 confers potent dual‐enzyme mimetic activities, scavenging superoxide anions and hydrogen peroxide through synergistic SOD‐like and CAT‐like catalysis. Notably, the thermal effect produced by near‐infrared irradiation further enhances the enzymatic activity of CuQ@SS31 itself. The nanozyme's crystalline properties ensure structural integrity and sustained catalytic durability. Furthermore, CuQ@SS31 has almost no effect on the cell‐protective heat shock protein 70 typically associated with free quercetin, thereby preserving essential thermal stress defenses. In addition, CuQ@SS31 also exhibits inherent antibacterial properties, reducing potential infection risks from intra‑articular administration. Finally, CuQ@SS31 effectively alleviated oxidative stress, suppressed inflammation, and decelerated cartilage degradation, while demonstrating prolonged joint retention and a favorable safety profile.