Abstract

Following ischemic stroke, excessive production of mitochondrial reactive oxygen species leads to oxidative stress and impaired mitophagy, which significantly hinders neurological recovery. Targeted delivery of therapeutics to the mitochondria of damaged neurons represents a promising strategy for ischemic stroke treatment; however, the blood-brain barrier substantially limits its application. In this study, we developed a mitochondria-targeted metal-phenolic nanozyme delivery system through chelation of Salvianolic Acid B with cerium ions. By leveraging the intranasal administration route—which can partially bypass the blood-brain barrier—this system facilitates direct nose-to-brain transport and enables mitochondrial delivery in the ischemic region, contributing to improved therapeutic outcomes in a rat model of ischemic stroke. Both in vitro and in vivo results demonstrate that the nanosystem synergistically ameliorates the mitochondrial microenvironment by suppressing oxidative stress and modulating autophagy, leading to significant neuroprotective effects. This study suggests a potential therapeutic approach for ischemic stroke using functional metal-phenolic nanozymes.