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The infiltration of neutrophils into the brain provides opportunities for regulatory drugs across the blood\u2013brain barrier, while hindered by neutrophil extracellular traps (NETs) and targeted delivery of intracerebral drugs to microglia. This study reports an efficient neutrophil hijacking nanoplatform (referred to as APTS) for targeted A151 (a telomerase repeat sequence) delivery to microglia without the generation of NETs. In the middle cerebral artery occlusion (MCAO)\u00a0mouse model, the delivery efficiency to ischemic stroke tissues increases by fourfold. APTS dramatically reduces the formation of NETs by 2.2\u2010fold via reprogramming NETosis to apoptosis in neutrophils via a reactive oxygen species scavenging\u2010mediated citrullinated histone 3 inhibition pathway. Noteworthy, A151 within neutrophils is repackaged into apoptotic bodies following the death pattern reprogramming, which, when engulfed by microglia, polarizes microglia to an anti\u2010inflammatory M2 phenotype. After four times treatment, the cerebral infarction area in the APTS group decreases by 5.1\u2010fold. Thus, APTS provides a feasible, efficient, and practical drug delivery approach for reshaping the immune microenvironment and treating brain disorders in the central nervous system.<\/jats:p>","DOI":"10.1002\/advs.202305877","type":"journal-article","created":{"date-parts":[[2024,3,6]],"date-time":"2024-03-06T02:45:55Z","timestamp":1709693155000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["A Neutrophil Hijacking Nanoplatform Reprograming NETosis for Targeted Microglia Polarizing Mediated Ischemic Stroke Treatment"],"prefix":"10.1002","volume":"11","author":[{"given":"Na","family":"Yin","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Zhengzhou University  Zhengzhou 450001 China"},{"name":"Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases Zhengzhou University  Zhengzhou 450001 China"},{"name":"Collaborative Innovation Center of New Drug Research and Safety 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