Ultra‐Small Copper‐Based Multienzyme‐Like Nanoparticles Protect Against Hepatic Ischemia‐Reperfusion Injury Through Scavenging Reactive Oxygen Species in Mice

Abstract Hepatic ischemia‐reperfusion injury (IRI) is a severe complication that occurs in the process of liver transplantation, hepatectomy, and other end‐stage liver disease surgery, often resulting in the failure of surgery operation and even patient death. Currently, there is no effective way to prevent hepatic IRI clinically. Here, it is reported that the ultra‐small copper‐based multienzyme‐like nanoparticles with catalase‐like (CAT‐like) and superoxide dismutase‐like (SOD‐like) catalytic activities significantly scavenge the surge‐generated endogenous reactive oxygen species (ROS) and effectively protects hepatic IRI. Density functional theory calculations confirm that the nanoparticles efficiently scavenge ROS through their synergistic effects of the ultra‐small copper SOD‐like activity and manganese dioxides CAT‐like activity. Furthermore, the results show that the biocompatible CMP NPs significantly protected hepatocytes from IRI in vitro and in vivo. Importantly, their therapeutic effect is much stronger than that of N ‐acetylcysteamine acid (NAC), an FDA‐approved antioxidative drug. Finally, it is demonstrated that the protective effects of CMP NPs on hepatic IRI are related to suppressing inflammation and hepatocytic apoptosis and maintaining endothelial functions through scavenging ROS in liver tissues. The study can provide insight into the development of next‐generation nanomedicines for scavenging ROS.