Nose-to-brain delivery of targeted lipid nanoparticles as two-pronged β-amyloid nanoscavenger for Alzheimer's disease therapy.
10.1016/j.apsb.2025.02.035
- Author:
Yanyan XU
1
;
Xiangtong YE
2
;
Yanfeng DU
1
;
Wenqin YANG
2
;
Fan TONG
2
;
Wei LI
1
;
Qianqian HUANG
2
;
Yongke CHEN
2
;
Hanmei LI
3
;
Huile GAO
2
;
Weiwei ZHANG
1
Author Information
1. School of Public Health, Chengdu Medical College, Chengdu 610500, China.
2. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan, Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
3. School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China.
- Publication Type:Journal Article
- Keywords:
Alzheimer's disease;
Lipid nanoparticle;
Nose-to-brain delivery;
Synergistic therapy;
Targeted delivery;
α-Mangostin;
β-Amyloid clearance;
β-Site APP cleaving enzyme 1
- From:
Acta Pharmaceutica Sinica B
2025;15(6):2884-2899
- CountryChina
- Language:English
-
Abstract:
Alzheimer's disease (AD), characterized by β-amyloid (Aβ) 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 Aβ 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 Aβ-induced low-density lipoprotein receptor downregulation, promoting microglial phagocytosis and autophagic degradation of Aβ, while siB effectively suppressed BACE1 expression, abrogating Aβ synthesis. In vivo investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery, substantial Aβ 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.
