A Neutrophil Hijacking Nanoplatform Reprograming NETosis for Targeted Microglia Polarizing Mediated Ischemic Stroke Treatment

Male 0301 basic medicine Neutrophils Science Q neutrophil extracellular traps microglia neutrophil hitchhiking Extracellular Traps Mice, Inbred C57BL Mice Disease Models, Animal 03 medical and health sciences Drug Delivery Systems drug delivery ischemic stroke Animals Nanoparticles Microglia Research Articles Ischemic Stroke
DOI: 10.1002/advs.202305877 Publication Date: 2024-03-06T07:45:55Z
ABSTRACT
AbstractPrecise and efficient regulation of microglia is vital for ischemic stroke therapy and prognosis. The infiltration of neutrophils into the brain provides opportunities for regulatory drugs across the blood–brain 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) mouse model, the delivery efficiency to ischemic stroke tissues increases by fourfold. APTS dramatically reduces the formation of NETs by 2.2‐fold via reprogramming NETosis to apoptosis in neutrophils via a reactive oxygen species scavenging‐mediated 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‐inflammatory M2 phenotype. After four times treatment, the cerebral infarction area in the APTS group decreases by 5.1‐fold. 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.
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