Bacteria-derived Outer-membrane Vesicles Hitchhike Neutrophils to Enhance Ischemic Stroke Therapy.

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, we propose a strategy 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 showed that OMV@PGZ simultaneously inhibited the activation of NLRP3 inflammasomes and ferroptosis and reduced the reperfusion injury to exert a neuroprotective effect. Notably, the transcription factors Pou2f1 and Nrf1 of oligodendrocytes were identified for the first time to be involved in this process and promoted neural repair by single-nucleus RNA sequencing (snRNA-seq). This article is protected by copyright. All rights reserved.