Neurophilic Biomimetic Lipoprotein‐Mediated Targeted Nerve Growth Factor Delivery for Traumatic Brain Injury Therapy

Abstract Traumatic brain injury (TBI) induces neuronal death, inflammation, and neurological dysfunction. Although nerve growth factor (NGF) possesses neuroprotective potential, its clinical use is hindered by poor blood‐brain barrier (BBB) permeability and insufficient neural targeting. Here, a neurophilic biomimetic lipoprotein for brain‐targeted NGF delivery is developed: 1) a matrix‐like core (Nc) that preserves NGF bioactivity; 2) an ApoE3‐reconstituted high‐density lipoprotein shell (Nc‐rHDL) to enhance BBB penetration; 3) an αRDP peptide‐modified version (Nc‐rHDL@P) to improve neural targeting. In vitro BBB models and controlled cortical impact (CCI) mice demonstrate that Nc‐rHDL@P efficiently crossed the BBB and selectively accumulated around injured regions. The engineered Nc‐rHDL@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‐rHDL@P effectively alleviated inflammation and glial scar formation while significantly increasing neuronal survival—ultimately 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‐targeted delivery of neurotrophins beyond NGF, offering a promising translational strategy for TBI and related neurological disorders.