Zhuang_2026_Neurosci.Lett__138623

Nerve agents represent a significant hazard to human health and safety. Prompt reactivation of inhibited cholinesterase is imperative; however, the blood-brain barrier (BBB) impedes the delivery of cholinesterase reactivators to the central nervous system. This study aimed to develop brain-targeted reconstituted lipid nanoparticles (rLNPs) loaded with HI-6 (rLNPs/HI-6), with the goal of enhancing central nervous system (CNS) delivery and improving reactivation efficacy in soman-poisoned mice. In healthy mice, rLNPs/HI-6 significantly enhanced BBB permeability to (11.47 +/- 1.62)% and blood-cerebrospinal fluid barrier (BCSFB) permeability to (24.46 +/- 2.65)%. In soman-poisoned mice (70% LD(50)), rLNPs/HI-6 further elevated BBB and BCSFB permeability to (22.95 +/- 2.89)% and (41.12 +/- 4.32)%. Importantly, rLNPs/HI-6 achieved a brain AChE relative activity of (36.17 +/- 1.95)%, which was 1.9-fold higher than that of free HI-6. These findings demonstrate that brain-derived rLNPs effectively enhance the CNS delivery efficiency of HI-6 and augment AChE reactivation efficacy by increasing BBB and BCSFB permeability, thereby offering a feasible strategy for central nervous system-targeted treatment of nerve agent poisoning.