Mitochondrial-targeting Mn3O4/UIO-TPP nanozyme scavenge ROS to restore mitochondrial function for osteoarthritis therapy

Abstract Excessive reactive oxygen species (ROS)-induced mitochondrial damage has impact on osteoarthritis (OA). Nanozyme mimics as natural enzyme alternatives to scavenge excessive ROS has offered a promising strategy for OA therapy. Herein, we reported a novel mitochondrial-targeting Mn3O4/UIO-TPP nanozyme using metal-organic frameworks with loaded Mn3O4 as the enzyme-like active core combining mitochondria-targeting triphenylphosphine (TPP) groups to serve as ROS scavengers for therapy of OA. With sequential catalysis of superoxide dismutase-like, catalase (CAT)-like, and hydroxyl radical (·OH) scavenging potentials, the nanozyme can target mitochondria by crossing subcellular barriers to effectively eliminate ROS to restore mitochondrial function and inhibit inflammation and chondrocyte apoptosis. It also has favorable biocompatibility and biosafety. Based on anterior cruciate ligament transection-induced OA joint models, this mitochondrial-targeting nanozyme effectively mitigated the inflammatory response with the Pelletier score reduction of 49.9% after 8-week therapy. This study offers a prospective approach to the design of nanomedicines for ROS-related diseases.