<p>Ischemic stroke remains a leading cause of death and disability, and current reperfusion therapies fail to control the oxidative and inflammatory cascades that drive secondary brain injury. Here, we engineer a brain-penetrating, reactive oxygen species (ROS)-responsive hybrid cell-liposome nanoplatform (A2-RLR@4P-PM) that targets multiple pathological events within a single system. The biomimetic nanoplatform combines a carrier-free supramolecular drug core with an Angiopep-2-functionalized red blood cell/liposome hybrid membrane, conferring prolonged circulation, immune evasion, efficient low-density lipoprotein receptor–related protein 1 (LRP1)-mediated blood–brain barrier transport, and ROS-triggered payload release. Upon accumulation in the ischemic brain, A2-RLR@4P-PM senses the oxidatively stressed microenvironment to rapidly liberate therapeutics and enables mild near-infrared photothermal activation to further enhance local delivery without thermal damage. The nanoplatform exhibits excellent hemocompatibility and cytocompatibility, suppresses ROS overproduction, preserves mitochondrial membrane potential, reprograms microglia from a pro-inflammatory M1 to a reparative M2 phenotype, and attenuates neuronal apoptosis. In a transient middle cerebral artery occlusion mouse model, A2-RLR@4P-PM preferentially accumulates in the ischemic hemisphere, reduces infarct volume, mitigates oxidative and apoptotic injury, preserves neuronal architecture, and markedly improves survival, neurological scores, motor function, and cognitive performance without evident systemic toxicity. These findings highlight a broadly applicable biomaterials-based strategy for advanced ischemic stroke therapy.</p> Graphical abstract <p></p>