Neutrophil-hitchhiking nanoplatform overcomes blood-brain barrier to treat cerebral ischemia-reperfusion injury via ferroptosis inhibition and microglial modulation.

Cerebral ischemia reperfusion injury (CIRI) after stroke is hard to treat because the blood-brain barrier (BBB) blocks most drugs, while reperfusion triggers oxidative stress, ferroptosis, and neuroinflammation. We designed a neutrophil hitchhiking lipid nanoparticle (RKH Neu@Mino) by conjugating an RKH peptide (from Akkermansia muciniphila) onto DSPE PEG maleimide and encapsulating minocycline via microfluidic assembly. The nanoparticles specifically bind to neutrophil TLR4, allowing activated neutrophils to ferry them across the BBB and into ischemic lesions. Once there, RKH Neu@Mino suppresses ROS burst, inhibits ferroptosis, and shifts microglial polarization from pro inflammatory M1 to protective M2 phenotype, thereby mitigating CIRI. This neutrophil hitchhiking strategy offers a powerful approach to overcome the BBB delivery hurdle and treat post stroke reperfusion injury.