Platinum‐Loaded Cerium Oxide Capable of Repairing Neuronal Homeostasis for Cerebral Ischemia‐Reperfusion Injury Therapy

Abstract Effective neuroprotective agents are required to prevent neurological damage caused by reactive oxygen species (ROS) generated by cerebral ischemia‐reperfusion injury (CIRI) following an acute ischemic stroke. Herein, it is aimed to develop the neuroprotective agents of cerium oxide loaded with platinum clusters engineered modifications (Pt n ‐CeO 2 ). The density functional theory calculations show that Pt n ‐CeO 2 could effectively scavenge ROS, including hydroxyl radicals (·OH) and superoxide anions (·O 2 − ). In addition, Pt n ‐CeO 2 exhibits the superoxide dismutase‐ and catalase‐like enzyme activities, which is capable of scavenging hydrogen peroxide (H 2 O 2 ). The in vitro studies show that Pt n ‐CeO 2 could adjust the restoration of the mitochondrial metabolism to ROS homeostasis, rebalance cytokines, and feature high biocompatibility. The studies in mice CIRI demonstrate that Pt n ‐CeO 2 could also restore cytokine levels, reduce cysteine aspartate‐specific protease (cleaved Caspase 3) levels, and induce the polarization of microglia to M2‐type macrophages, thus inhibiting the inflammatory responses. As a result, Pt n ‐CeO 2 inhibits the reperfusion‐induced neuronal apoptosis, relieves the infarct volume, reduces the neurological severity score, and improves cognitive function. Overall, these findings suggest that the prominent neuroprotective effect of the engineered Pt n ‐CeO 2 has a significant neuroprotective effect and provides a potential therapeutic alternative for CIRI.