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

Alzheimer's disease (AD), characterized by -amyloid (A) 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 -mangostin (-M) and -site APP cleaving enzyme 1 (BACE1) siRNA (siB). This dual-modal therapeutic system synergistically combines the neuroprotective and microglia-reprogramming capabilities of -M with the transcriptional silencing of BACE1 siB, thereby simultaneously inhibiting A production and enhancing its clearance. Fabricated 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. studies demonstrated that -M reversed A-induced low-density lipoprotein receptor downregulation, promoting microglial phagocytosis and autophagic degradation of A, while siB effectively suppressed BACE1 expression, abrogating A synthesis. investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery, substantial A 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.