Inhibiting Mitochondrial Damage for Efficient Treatment of Cerebral Ischemia‐Reperfusion Injury Through Sequential Targeting Nanomedicine of Neuronal Mitochondria in Affected Brain Tissue

Abstract Oxidative stress, predominantly from neuronal mitochondrial damage and the resultant cytokine storm, is central to cerebral ischemia‐reperfusion injury (CIRI). However, delivering drugs to neuronal mitochondria remains challenging due to the blood‐brain barrier (BBB), which impedes drug entry into affected brain tissues. This study introduces an innovative tannic acid (TA) and melanin‐modified heteropolyacid nanomedicine (MHT), which highly specifically eliminates the neuronal mitochondrial reactive oxygen radicals burst to efficiently reduce neuronal mitochondrial damage through a strategically designed sequential targeting strategy from affected brain tissue to neuronal mitochondria. TA endows MHT with sequential targeting ability by binding to matrix proteins exposed to the damaged BBB and mitochondrial outer membrane proteins of neurons, while melanin significantly enhances the antioxidant capacity of MHT. Consequently, MHT effectively inhibits neuronal apoptosis by protecting mitochondria and reversing the inflammatory immune environment through the deactivation of the cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway. MHT demonstrated a strong therapeutic effect on CIRI, with an ultralow dose (2 mg kg −1 ) proving effective in reversing the condition. This work not only introduces a new avenue to significantly reduce CIRI through sequential targeting therapy but also offers a new paradigm for treating other ischemia‐reperfusion injury diseases.