A dual-targeting nanozyme platform integrating macrophage hitchhiking and TfR transcytosis for precision therapy of ischemic stroke

Ischemic stroke, a critical neurological disorder resulting from abrupt cerebral blood flow interruption, remains a leading cause of global mortality and chronic disability. Despite advancements in reperfusion therapies, many survivors still suffer significant neurological deficits, primarily attributed to ischemia-reperfusion injury-induced oxidative stress and neuroinflammation. To address these challenges, we designed cerium-curcumin hybrid nanoparticles (Ce-Cur NPs) by leveraging the coordination interaction between redox-active cerium ions and curcumin’s β-diketone moiety. These Ce-Cur NPs were engineered to alleviate ROS-mediated secondary injuries and promote neural repair by leveraging their remarkable ROS scavenging capabilities, which mimic enzymatic activities to effectively neutralize superoxide and hydroxyl radicals. Furthermore, M1 polarized macrophage-derived membranes were employed to enhance the targeted delivery of Ce-Cur NPs to ischemic regions, while transferrin receptor (TfR)-activated peptides enabled efficient receptor-mediated transcytosis across the blood-brain barrier. In vivo studies using a middle cerebral artery occlusion (MCAO) model demonstrated that TfR-M 1 -Ce-Cur NPs successfully localized to the ischemic brain, significantly reduced infarct volume, and preserved neuronal integrity. Enhanced neurogenesis and improved functional recovery were observed, underscoring the therapeutic potential of Ce-Cur NPs as a versatile platform for ischemic stroke treatment. This approach provides a robust and evidence-based solution to enhance clinical outcomes for patients with ischemic stroke.