Blood–Brain Barrier‐Penetrating and Lesion‐Targeting Nanoplatforms Inspired by the Pathophysiological Features for Synergistic Ischemic Stroke Therapy

Abstract Ischemic stroke is a dreadful vascular disorder that poses enormous threats to the public health. Due to its complicated pathophysiological features, current treatment options after ischemic stroke attack remains unsatisfactory. Insufficient drug delivery to ischemic lesions impeded by the blood–brain barrier (BBB) largely limits the therapeutic efficacy of most anti‐stroke agents. Herein, inspired by the rapid BBB penetrability of 4T1 tumor cells upon their brain metastasis and natural roles of platelet in targeting injured vasculatures, a bio‐derived nanojacket is developed by fusing 4T1 tumor cell membrane with platelet membrane, which further clothes on the surface of paeonol and polymetformin‐loaded liposome to obtain biomimetic nanoplatforms (PP@PCL) for ischemic stroke treatment. The designed PP@PCL could remarkably alleviate ischemia‐reperfusion injury by efficiently targeting ischemic lesion, preventing neuroinflammation, scavenging excess reactive oxygen species (ROS), reprogramming microglia phenotypes, and promoting angiogenesis due to the synergistic therapeutic mechanisms that anchor the pathophysiological characteristics of ischemic stroke. As a result, PP@PCL exerts desirable therapeutic efficacy in injured PC12 neuronal cells and rat model of ischemic stroke, which significantly attenuates neuronal apoptosis, reduces infarct volume, and recovers neurological functions, bringing new insights into exploiting promising treatment strategies for cerebral ischemic stroke management.