Multi-functional bionic nanoparticles for precise neuronal targeting and synergistic therapy in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by core pathological mechanisms including amyloid-β plaque aggregation, cholinergic dysfunction, and neuronal apoptosis. Given the complex interplay of these pathways, combination therapies are emerging as more effective strategies than single-target approaches. The success of such therapies depends on rational target selection and optimal regimen design. Herein, we developed a multifunctional biomimetic nanocarrier, B6/Tet1-RBCm-NPs (BTRN), for precise neuron-targeted combination therapy. The nanoparticles (NPs) core was fabricated using safe, biocompatible poly (lactic-co-glycolic acid) (PLGA) to co-deliver natural product genistein and mature marketed donepezil, which act synergistically to enhance therapeutic efficacy. The core was further modified with endogenous red blood cell membranes, providing effective immune evasion and a prolonged circulation lifetime. Functionalization with the blood-brain barrier (BBB)-penetrating peptide B6 and the neuron-targeting peptide Tet1 confers excellent BBB penetration and specific accumulation in diseased neurons. Collectively, BTRN treats AD through multiple mechanisms, including reducing Aβ production, regulating cholinergic function, and inhibiting neuronal apoptosis. This biomimetic system presents a promising therapeutic strategy and offers valuable insights for the clinical translation of combination therapies in AD.