Se‐Containing MOF Coated Dual‐Fe‐Atom Nanozymes With Multi‐Enzyme Cascade Activities Protect Against Cerebral Ischemic Reperfusion Injury

Abstract The atomically monodispersed dual‐atom nanozyme not only possesses the advantages of homogeneous active centers and high atomic utilization efficiency but also exhibits amazing synergistic effect for higher catalytic activities than single‐atom nanozyme. However, how to construct dual‐atom nanozyme with multi‐enzyme cascade capacity for protecting against brain tissue damage is a great challenge. Herein, for coping with the secondary damage to brain tissue caused by the explosive generation of reactive oxygen species(ROS) during cerebral ischemia‐reperfusion, a multi‐enzyme cascade antioxidant system is constructed by encapsulating dual‐Fe‐atom nanozyme (Fe 2 NC) in a selenium‐containing MOF (Se‐MOF) shell layer. The designed dual‐Fe‐atom nanozyme exhibits higher superoxide dismutase‐like, catalase‐like, and even oxidase‐like activities than single‐atom Fe (Fe 1 NC) nanozyme, and moreover, the Se‐MOF shell layer not only acts as a glutathione peroxidase mimic, but also improves the stability and biocompatibility of the Fe 2 NC nanozyme obviously. The synergistic effect of Fe 2 NC has been demonstrated to be the main reason for the higher activity by density functional theory calculations. In vitro and in vivo results reveal that the multifunctional antioxidant Fe 2 NC@Se nanoparticles can counteract oxidative damage and inhibit neural apoptosis after cerebral ischemia‐reperfusion injury by effectively eliminating intracellular ROS and potentially inhibiting the ASK1/JNK apoptotic signaling pathway.