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Although nerve growth factor (NGF) possesses neuroprotective potential, its clinical use is hindered by poor blood\u2010brain barrier (BBB) permeability and insufficient neural targeting. Here, a neurophilic biomimetic lipoprotein for brain\u2010targeted NGF delivery is developed: 1) a matrix\u2010like core (Nc) that preserves NGF bioactivity; 2) an ApoE3\u2010reconstituted high\u2010density lipoprotein shell (Nc\u2010rHDL) to enhance BBB penetration; 3) an \u03b1RDP peptide\u2010modified version (Nc\u2010rHDL@P) to improve neural targeting. In vitro BBB models and controlled cortical impact (CCI) mice demonstrate that Nc\u2010rHDL@P efficiently crossed the BBB and selectively accumulated around injured regions. The engineered Nc\u2010rHDL@P significantly enhances the survival of injured neurons, promotes neurite outgrowth in PC12 cells, and facilitates the neuronal differentiation of human neural stem cells (hNSCs) and Schwann cells in vitro. In vivo studies confirm that Nc\u2010rHDL@P effectively alleviated inflammation and glial scar formation while significantly increasing neuronal survival\u2014ultimately facilitating the recovery of motor function, spatial learning, and memory in CCI model mice. Collectively, this neurophilic biomimetic lipoprotein platform demonstrates broad potential for brain\u2010targeted delivery of neurotrophins beyond NGF, offering a promising translational strategy for TBI and related neurological disorders.<\/jats:p>","DOI":"10.1002\/advs.202509405","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T10:05:21Z","timestamp":1755511521000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Neurophilic Biomimetic Lipoprotein\u2010Mediated Targeted Nerve Growth Factor Delivery for Traumatic Brain Injury Therapy"],"prefix":"10.1002","volume":"12","author":[{"given":"Jialin","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Renji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 200127 China"},{"name":"Shanghai Institute of Head Trauma  Shanghai 200127 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