Bimetallic Single-Atom Nanozyme with Enhanced Multienzyme-Mimicking Activity for Osteoarthritis Treatment via Reprogramming Inflammatory and Metabolic Microenvironment

Osteoarthritis (OA) is a degenerative whole-joint disease. The overproduced reactive oxygen species (ROS)-induced chondrocyte inflammation and metabolic imbalance play crucial roles in its occurrence and progression. Although nanozymes with ROS scavenging activity offer a promising approach for OA treatment, the previously reported nanozymes suffer from suboptimal ROS scavenging activity due to single and insufficient exposure of active sites, thereby impeding their application. Herein, a bimetallic single-atom copper-manganese nanozyme (Cu-Mn NE) was designed to mimic superoxide dismutase (SOD) and catalase (CAT) activity for OA therapy. The introduction of Mn facilitated electron transfer to Cu and modulated the d-band center of Cu, which enhanced the adsorption energy of ROS and decreased the reaction energy barriers. The synergistic interplay between Cu and Mn and ultrahigh active-atom utilization endowed Cu-Mn NE with higher ROS scavenging efficiency than the monometallic Cu or Mn nanozyme. <i>In vitro</i> results indicated that the Cu-Mn NE could protect cells from ROS-mediated oxidative damage. More importantly, Cu-Mn NE reprogrammed the pro-inflammatory M1 macrophage toward anti-inflammatory M2 subtype, reduced pro-inflammatory cytokine secretion, increased cartilage regeneration-related collagen II and aggrecan expression, and inhibited cartilage degeneration-related hydrolase synthesis, ultimately rescuing cartilage inflammation and metabolic homeostasis. <i>In vivo</i> results showed that Cu-Mn NE alleviated pathological features of OA and improved joint function, thus delaying OA progression. Overall, this study presents innovative insights into nanoenzyme design and offers potential approaches for treating OA and other inflammation-related diseases.