Nose-to-brain delivery of targeted lipid nanoparticles as two-pronged β-amyloid nanoscavenger for Alzheimer's disease therapy

Alzheimer's disease (AD), characterized by <i>β</i>-amyloid (A<i>β</i>) aggregation and neuroinflammation, remains a formidable clinical challenge. Herein, we present an innovative nose-to-brain delivery platform utilizing lactoferrin (Lf)-functionalized lipid nanoparticles (LNPs) co-encapsulating <i>α</i>-mangostin (<i>α</i>-M) and <i>β</i>-site APP cleaving enzyme 1 (BACE1) siRNA (siB). This dual-modal therapeutic system synergistically combines the neuroprotective and microglia-reprogramming capabilities of <i>α</i>-M with the transcriptional silencing of BACE1 <i>via</i> siB, thereby simultaneously inhibiting A<i>β</i> production and enhancing its clearance. Fabricated <i>via</i> a microfluidic approach, the LNPs exhibited uniform particle size distribution, great encapsulation efficiency, and robust colloidal stability. Upon intranasal administration, Lf-functionalization enabled superior brain-targeting efficacy through receptor-mediated transcytosis. <i>In vitro</i> studies demonstrated that <i>α</i>-M reversed A<i>β</i>-induced low-density lipoprotein receptor downregulation, promoting microglial phagocytosis and autophagic degradation of A<i>β</i>, while siB effectively suppressed BACE1 expression, abrogating A<i>β</i> synthesis. <i>In vivo</i> investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery, substantial A<i>β</i> plaque reduction, and alleviation of neuroinflammation and oxidative stress. This intricately designed LNP system, exploiting a non-invasive and efficient nose-to-brain delivery route, provides a biocompatible, synergistic, and transformative therapeutic strategy for the multifaceted management of AD.