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Current therapeutic strategies for HIE are largely limited to supportive care and therapeutic hypothermia, which fail to effectively target these mechanisms. To address this challenge, we developed a microglia\u2010derived exosome\u2013liposome hybrid membrane systems (HMS) (R+si@LPs\u2010TK\/TAT+Exo, abbreviated as Rs@LP\u2010T\/T\u2010E) for the co\u2010delivery of resveratrol (RES) and acyl\u2010CoA synthetase long\u2010chain family member 4 (ACSL4) siRNA. The nanosystem exhibited favorable stability, reactive oxygen species (ROS)\u2010responsive drug release, and efficient blood\u2013brain barrier (BBB) penetration, enabling targeted accumulation within ischemic brain regions. In experimental models, Rs@LP\u2010T\/T\u2010E significantly attenuated neuroinflammation and ferroptosis, promoted microglial polarization toward the anti\u2010inflammatory M2 microglial phenotype, and restored mitochondrial function, thereby reducing cerebral infarct volume and improving cerebral perfusion. In conclusion, this study presents an efficient, targeted, and biocompatible nanodelivery strategy that holds strong translational potential for HIE therapy.<\/jats:p>","DOI":"10.1002\/adhm.71060","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:04:02Z","timestamp":1774271042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Engineered Microglial Exosome\u2013Liposome Hybrid Nanovesicles for Synergistic Therapy of Hypoxic\u2010Ischemic Encephalopathy by Dual\u2010Targeting Ferroptosis and Neuroinflammation"],"prefix":"10.1002","volume":"15","author":[{"given":"Chanyue","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangqian","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changfeng","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liguo","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The 960th Hospital of the PLA Joint Logistics Support Force  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caifan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weipeng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaojuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Basic Medicine School of Basic Medical Sciences Shandong Medical College  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiacan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Shandong First Medical University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery The First Affiliated Hospital of Shandong First Medical University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8078-1075","authenticated-orcid":false,"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/BIOMEDICINES13061431"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.HELIYON.2024.E34121"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/FPHAR.2024.1417532"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/S41420\u2010024\u201002014\u20102"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.REDOX.2024.103185"},{"issue":"1","key":"e_1_2_11_7_1","first-page":"1","article-title":"Resveratrol Used as Nanotherapeutic: A Promising Additional Therapeutic Tool Against Hormone\u2010Sensitive, Hormone\u2010Insensitive and Resistant Prostate Cancer","volume":"11","author":"Badawi J. 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