Phyhip‐Targeted Delivery of bFGF Platform with Dual Modulation for Enhancing Neurovascular Repair in Traumatic Brain Injury

Traumatic brain injury (TBI) remains a critical neurosurgical challenge with limited therapeutic options. While basic fibroblast growth factor (bFGF) demonstrates neuroprotective and angiogenic potential, its clinical translation is hindered by nonspecific biodistribution and poor blood-brain barrier (BBB) penetration. In the present study, a brain-targeted recombinant protein (AcuP-bFGF) is developed by fusing bFGF with an acute peptide (SLYGSSRHTAPISF, named as AcuP), which enables Phyhip-mediated active transport across the compromised BBB while preserving the bioactivity of bFGF and prolonging its half-life in vivo. Employing Immunoprecipitation-mass spectrometry (IP-MS), phantom-CoA 2-hydroxylase-interacting 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-targeted 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-pathway modulation: pro-regenerative activation of NRG1-ErbB4-AKT signaling coupled with anti-inflammatory suppression of cGAS-STING-NFκB cascade. Therefore, the targeted delivery of AcuP-bFGF can represent a potential therapeutic approach for TBI, addressing both neuronal survival and neuroinflammation via Phyhip-mediated bFGF delivery and crosstalk in neuroimmune pathways.