Active Transport of Biomimetic Cascaded Nanozymes Across Blood–Brain Barrier to Scavenge ROS and Alleviate Neuroinflammation Against Cerebral Ischemia Reperfusion Injury

Abstract The rational design of potent antioxidative agents with active transport across blood–brain barrier (BBB) is critically required for mitigating ischemic reperfusion‐induced reactive oxygen species (ROS)‐mediated neuroinflammation and neural injury in ischemic stroke therapy. Herein, a biomimetic nanozyme is engineered by integrating copper and selenium, key catalytic sites of natural antioxidant superoxide dismutase and glutathione peroxidase, into mesoporous polydopamine scaffolds (mPDA‐Cu/Se), yielding cascaded enzymatic activities for robust ROS scavenging. This nanozyme is further functionalized with a BBB‐penetrating peptide RVG29 and biocompatible red blood cell membrane (T‐mPDA‐Cu/Se) for enhanced BBB penetration and ischemic neuronal tissues accumulation in a transient middle cerebral artery occlusion rat model, where it effectively mitigates oxidative damage and neuron apoptosis. T‐mPDA‐Cu/Se also mitigates neuroinflammation‐induced injury by inhibiting astrocyte activation, microglia pro‐inflammatory polarization, and proinflammatory cytokines secretion, thus achieving reduced infarct volume and improved neuronal recovery without noticeable systemic toxicity. Collectively, this study provides a promising neuroprotective approach against reperfusion‐induced neuron injury in ischemic stroke.