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Current nanosystem\u2010based therapeutic strategies are mainly confined within the blood\u2010brain barrier (BBB), ignoring the constant intrusion from external challenges. Here, considering the unique vascular localization of NETs, a DNase I\u2010mediated NETs\u2010targeting nanoparticle is developed to integrate the catalytic and chemotactic functions of DNase I and achieve the synergistic regulation of the internal and external microenvironment of the neurovascular unit (NVU). DNase I navigates the nanoparticles to the lesion, enabling the accumulation in the brain through damaged BBB. The removal of intravascular NETs mitigates the ongoing destruction of the endothelium and reduces the recruitment of immunothrombosis. The main nanoparticles with dual antioxidant activity rescue neuronal apoptosis by scavenging reactive oxygen species (ROS) and protecting mitochondria. Reduced infarct size and remodeling of microenvironment homeostasis shown in the middle cerebral artery occlusion\/reperfusion (MCAO) mouse model. This strategy provides new insights into the vascular side treatment of ischemic stroke. Targeting mediated by enzyme chemotaxis is first validated and showed the potential of a universal chemotactic targeted delivery strategy.<\/jats:p>","DOI":"10.1002\/advs.202503689","type":"journal-article","created":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T10:10:51Z","timestamp":1751191851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["DNase I\u2010Mediated Chemotactic Nanoparticles for NETs Targeting and Microenvironment Remodeling Treatment of Acute Ischemic Stroke"],"prefix":"10.1002","volume":"12","author":[{"given":"Tongyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics School of Pharmaceutical Sciences Fudan University Shanghai 201203 China"},{"name":"Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Brain Function and Disorders Shanghai 201203 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