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However, effective NVU repair remains challenging due to the multifactorial nature of secondary injury. Here, a novel multimodal nanotherapeutic platform designed to concurrently target multiple key pathological events underlying NVU disruption is presented. This nanodrug integrates ultrasmall cerium oxide nanoparticles and IRAK\u20104 siRNA within a ROS\u2010responsive poly(1,4\u2010phenyleneacetone dimethylene thioketal) (PPADT) matrix, cloaked with neutrophil membranes for inflammation homing. At the injury lesion, the responsive nature enables on\u2010demand drug release, eliciting synergistic therapeutic actions. Specifically, the cerium nanodots catalyze ROS scavenging and oxygen generation, alleviating oxidative stress and hypoxia to facilitate blood\u2013brain barrier restoration, pericyte repair, and improved cerebral perfusion. Simultaneously, IRAK\u20104 siRNA downregulates pro\u2010inflammatory signaling and reprograms microglia toward an anti\u2010inflammatory phenotype. In a murine TBI model, the nanotherapy promotes vascular repair, reduces brain edema, attenuates neuroinflammation, and preserves neuronal integrity. Additionally, treatment ameliorates sleep spindle loss, reduces epileptiform activity, and significantly improves cognitive performance in learning and memory tasks. This work highlights a multipronged therapeutic strategy capable of restoring NVU homeostasis and mitigating secondary brain injury, offering great promise for advancing TBI treatment.<\/jats:p>","DOI":"10.1002\/adma.202509444","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T12:42:47Z","timestamp":1758717767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Multimodal Nanoregulator Rescues Impaired Neurovascular Units to Attenuate Secondary Injury Following Traumatic Brain Injury"],"prefix":"10.1002","volume":"38","author":[{"given":"Pengcheng","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Advanced Medical Materials and Devices Tianjin Key Laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy Institute of Biomedical Engineering Chinese Academy of Medical Sciences and Peking Union Medical College  Tianjin 300192 China"},{"name":"Department of Anesthesiology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Tianjin Institute of Anesthesiology Tianjin Medical University General Hospital  Tianjin 300071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueping","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Medical Materials and Devices Tianjin Key Laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy Institute of Biomedical Engineering Chinese Academy of Medical Sciences and Peking Union Medical College  Tianjin 300192 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yigang","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Medical Materials and Devices Tianjin Key Laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy Institute of Biomedical Engineering Chinese Academy of Medical Sciences and Peking Union Medical College  Tianjin 300192 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxiang","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Yantai Yuhuangding Hospital  Yantai Shandong 264000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pain Management Beijing Tiantan Hospital Capital Medical University  Beijing 100070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Advanced Medical Materials and Devices Tianjin Key Laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy Institute of Biomedical Engineering Chinese Academy of Medical Sciences and Peking Union Medical College  Tianjin 300192 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100070 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7597-9725","authenticated-orcid":false,"given":"Ji","family":"Qi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology Key Laboratory of Bioactive Materials Ministry of Education College of Life Sciences and Academy for Advanced Interdisciplinary Studies Nankai University  Tianjin 300071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30371-X"},{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30415-0"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X15666170613083606"},{"key":"e_1_2_8_2_2","first-page":"546","volume":"47","author":"Marshall L. 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