Blood-Brain Barrier Bypass via Intranasal Delivery Enables Sequentially Mitochondria-Targeted Bioengineered Nanolamellar for Ischemic Stroke therapy

Oxidative stress, triggered by neuronal mitochondrial damage and inflammatory storm, is the central pathological mechanism underlying cerebral ischemia-reperfusion (I/R) injury. Targeted delivery of anti-stroke agents to neuronal mitochondria after ischemia holds great promise for effective I/R injury treatment. However, the blood-brain barrier (BBB) poses a major obstacle, severely restricting drug delivery to ischemic brain regions, thereby causing insufficient drug accumulation in neuronal mitochondria. Herein, we develop a bioengineered nanolamellar (MM@BPPF) by coating microglia-mitochondria hybrid biomembrane onto black phosphorus nanosheets (BP NSs) loaded with polymetformin (PolyMet) and fingolimod hydrochloride (FTY720). Specifically, microglia membrane (MicM) facilitates inflammation-directed targeting to the injured brain regions, while mitochondria membrane (MitM) provides homotypic targeting to neuronal mitochondria. Meanwhile, BP NSs significantly enhance the antioxidant capacity of MM@BPPF, whereas PolyMet and FTY720 synergistically suppress neuroinflammation and modulate microglial polarization. More importantly, intranasal administration enables MM@BPPF to bypass the BBB, substantially improving brain-targeting efficiency and avoiding first-pass metabolism. Consequently, MM@BPPF exerts potent neuroprotective effects by scavenging excessive reactive oxygen species, restoring mitochondrial function, alleviating neuroinflammation, and modulating cerebral ischemic microenvironment. Collectively, 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.