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While basic fibroblast growth factor (bFGF) demonstrates neuroprotective and angiogenic potential, its clinical translation is hindered by nonspecific biodistribution and poor blood\u2010brain barrier (BBB) penetration. In the present study, a brain\u2010targeted recombinant protein (AcuP\u2010bFGF) is developed by fusing bFGF with an acute peptide (SLYGSSRHTAPISF, named as AcuP), which enables Phyhip\u2010mediated active transport across the compromised BBB while preserving the bioactivity of bFGF and prolonging its half\u2010life in vivo. Employing Immunoprecipitation\u2010mass spectrometry (IP\u2010MS), phantom\u2010CoA 2\u2010hydroxylase\u2010interacting protein (Phyhip) is identified as the molecular target of AcuP in TBI. This discovery defines a new targeting axis for TBI intervention that overcomes the traditional BBB penetration challenges. A comprehensive study demonstrates that Phyhip\u2010targeted delivery of engineered bFGF exerts significant effects, including enhanced neuronal survival, increased neovascularization, restored BBB integrity, and suppressed neuroinflammation. These effects ultimately promote the recovery of motor function in rats with TBI. Transcriptomic profiling reveals dual\u2010pathway modulation: pro\u2010regenerative activation of NRG1\u2010ErbB4\u2010AKT signaling coupled with anti\u2010inflammatory suppression of cGAS\u2010STING\u2010NF\u03baB cascade. Therefore, the targeted delivery of AcuP\u2010bFGF can represent a potential therapeutic approach for TBI, addressing both neuronal survival and neuroinflammation via Phyhip\u2010mediated bFGF delivery and crosstalk in neuroimmune pathways.<\/jats:p>","DOI":"10.1002\/adhm.202502075","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T10:27:20Z","timestamp":1754908040000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Phyhip\u2010Targeted Delivery of bFGF Platform with Dual Modulation for Enhancing Neurovascular Repair in Traumatic Brain Injury"],"prefix":"10.1002","volume":"14","author":[{"given":"Weihong","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Human Anatomy Histology and Embryology School of Basic Medicine Qingdao University  Qingdao 266071 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