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

作者：Yanyan Xu, X W Ye, Yanfeng Du, Wenqin Yang, Fan Tong, Wei Li, Qianqian Huang, Yongke Chen, Hanmei Li, Huile Gao, Weiwei Zhang · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.02.035 · 被引用次数：41 · 研究领域：Alzheimer's disease research and treatments、Amyloidosis: Diagnosis, Treatment, Outcomes、Lipid Membrane Structure and Behavior

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