Bacteria‐Derived Outer‐Membrane Vesicles Hitchhike Neutrophils to Enhance Ischemic Stroke Therapy

Abstract The treatment of reperfusion injury after ischemic stroke remains unsatisfactory since the blood‐brain barrier (BBB) prevents most neuroprotective agents from entering the brain. Here, a strategy is proposed based on bacteria‐derived outer‐membrane vesicle (OMV) hitchhiking on the neutrophils for enhanced brain delivery of pioglitazone (PGZ) to treat ischemic stroke. By encapsulating PGZ into OMV, the resulting OMV@PGZ nanoparticles inherit the functions associated with the bacterial outer membrane, making them ideal decoys for neutrophil uptake. The results show that OMV@PGZ simultaneously inhibits the activation of nucleotide oligomerization‐like receptor protein 3 (NLRP3) inflammasomes and ferroptosis and reduces the reperfusion injury to exert a neuroprotective effect. Notably, the transcription factors Pou2f1 and Nrf1 of oligodendrocytes are identified for the first time to be involved in this process and promoted neural repair by single‐nucleus RNA sequencing (snRNA‐seq).