Angiopep-2 modified naringin nanoparticles for Alzheimer’s disease therapy overcoming BBB

Naringin (4′,5,7-trihydroxyflavanone-7-rhamnoglucoside, NG), a potential treatment for Alzheimer’s disease (AD), has strong neuroprotective effects but is limited by poor solubility, low bioavailability, and limited brain accumulation. To address these issues, we developed ANG-NG-NPs, a novel NG-loaded poly (ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) nanoparticle modified with the brain-targeting peptide Angiopep-2 (TFFYGGSRGKRNNFKTEEY, ANG). ANG-NG-NPs exhibited an average size of 126.1 ± 4.50 nm, a zeta potential of −2.97 ± 0.29 mV, 73.43 ± 0.80% encapsulation efficiency (EE), and 24.68 ± 0.45% drug loading capacity (LC). <i>In vitro</i> release studies confirmed its sustained-release properties. <i>In vivo</i>, ANG-NG-NPs extended NG’s circulation time and increased brain uptake. Notably, ANG-NG-NPs restored learning and memory in APP/PS1 mice, improved hippocampal cell health, and reduced hyperphosphorylated tau protein (p-Tau) expression. These findings suggest ANG-NG-NPs as a promising brain-targeting system for treating central nervous system disorders.