Intranasal blood-brain barrier bypass enables sequential mitochondria-targeted bioengineered nanolamellar system for ischemic stroke therapy

Mitochondrial damage constitutes the central pathological mechanism of cerebral ischemia-reperfusion (I/R) injury. Targeted delivery of antioxidants to mitochondria and the phenotype polarization of glial cells holds great promise for effective treatment. However, the blood-brain barrier (BBB) remains a major obstacle, causing insufficient drug accumulation in neuronal mitochondria. Here, we develop a bioengineered nanolamellar system (MM@BPPF) by coating microglia-mitochondria hybrid biomembrane onto black phosphorus nanosheets (BP NSs) loaded with polymetformin (PolyMet) and fingolimod hydrochloride (FTY720). Microglia membrane facilitates inflammation-directed targeting to the injured brain regions, while mitochondria membrane confers homotypic targeting to mitochondria. Meanwhile, BP NSs, PolyMet, and FTY720 act sequentially to restore mitochondrial function of neuronal cells and modulate microglial polarization. Intranasal administration enables MM@BPPF to bypass the BBB, substantially improving brain-targeting efficiency. This work not only offers an innovative sequential targeting strategy for mitigating I/R injury but also presents a potential paradigm for treating other central nervous system disorders.