Specifically Breaking Through the Injured Blood‐Brain Barrier With Tannic Acid‐Based Nanomedicine for Ischemic Stroke Ischemia Reperfusion Treatment

ABSTRACT Protecting neuronal mitochondria by eliminating the mitochondrial ROS (mtROS) storm is crucial to abrogate the neuronal damage cascade of ischemic stroke ischemia reperfusion (ISIR), which is a long‐standing challenge in the field of ischemic stroke (IS). Existing blood‐brain barrier (BBB) penetration methods are usually unable to distinguish between healthy brain tissue and cerebral infarction tissue, and BBB targeting is not compatible with mitochondrial targeting, resulting in a huge barrier to the specific elimination of mtROS in neuronal mitochondria in ISIR. This study introduces an elegantly designed tannic acid, polydopamine, and Mo‐based heteropolyacid ternary composite nanomedicine (TPM), which not only has a superb ability to eliminate multiple ROS thanks to the introduction of polydopamine, but also can actively recognize the injured BBB site, specifically enter the neurons in the cerebral infarction area, and then highly specifically target the mitochondria of neurons to efficiently eliminate mtROS. TPM could significantly inhibit neuronal apoptosis by protecting mitochondria and eliminate inflammation by inhibiting activation of the STING pathway, thereby significantly reducing the size of cerebral infarction. This sequential targeting of TPM from the injured BBB to neuronal mitochondria provides a promising strategy to treat ISIR in the clinical setting.