Blood‐Brain Barrier‐Penetrating Metal‐Organic Framework Antioxidant Nanozymes for Targeted Ischemic Stroke Therapy

Abstract Overproduction of reactive oxygen species (ROS) during reperfusion in ischemic stroke (IS) severely impedes neuronal survival and results in high rates of morbidity and disability. The effective blood‐brain barrier (BBB) penetration and brain delivery of antioxidative agents remain the biggest challenge in treating ischemic reperfusion‐induced cerebrovascular and neural injury. In this study, a metal‐organic framework (MOF) nanozyme (MIL‐101‐NH 2 (Fe/Cu)) with ROS scavenging activities to encapsulate neuroprotective agent rapamycin is fabricated and decorating the exterior with BBB‐targeting protein ligands (transferrin), thereby realizing enhanced drug retention and controlled release within ischemic lesions for the synergistic treatment of IS. Through the receptor‐mediated transcellular pathway, the transferrin‐coated MOF nanoparticles achieved efficient transport across the BBB and targeted accumulation at the cerebral ischemic injury site of mice with middle cerebral artery occlusion/reperfusion (MCAO/R), wherein the nanocarrier exhibited catalytic activities of ROS decomposition into O 2 and H 2 O 2 ‐responsive rapamycin release. By its BBB‐targeting, antioxidative, anti‐inflammatory, and antiapoptotic properties, the MOF nanosystem addressed multiple pathological factors of IS and realized remarkable neuroprotective effects, leading to the substantial reduction of cerebral infarction volume and accelerated recovery of nerve functions in the MCAO/R mouse model. This MOF‐based nanomedicine provides valuable design principles for effective IS therapy with multi‐mechanism synergies.