Blood-brain barrier–penetrating siRNA nanomedicine for Alzheimer’s disease therapy

作者：Yutong Zhou, Feiyan Zhu, Yang Liu, Meng Zheng, Yibin Wang, Dongya Zhang, Yasutaka Anraku, Yan Zou, Jia Li, Haigang Wu, Xiaobin Pang, Wei Tao, Olga Shimoni, Ashley Ian Bush, Xue Xue, Bingyang Shi · 发表于：Science Advances · 年份：2020 · DOI：10.1126/sciadv.abc7031 · 被引用次数：300 · 研究领域：RNA Interference and Gene Delivery、Graphene and Nanomaterials Applications、Alzheimer's disease research and treatments

Toxic aggregated amyloid-β accumulation is a key pathogenic event in Alzheimer's disease (AD), which derives from amyloid precursor protein (APP) through sequential cleavage by BACE1 (β-site APP cleavage enzyme 1) and γ-secretase. Small interfering RNAs (siRNAs) show great promise for AD therapy by specific silencing of BACE1. However, lack of effective siRNA brain delivery approaches limits this strategy. Here, we developed a glycosylated "triple-interaction" stabilized polymeric siRNA nanomedicine (Gal-NP@siRNA) to target BACE1 in APP/PS1 transgenic AD mouse model. Gal-NP@siRNA exhibits superior blood stability and can efficiently penetrate the blood-brain barrier (BBB) via glycemia-controlled glucose transporter-1 (Glut1)-mediated transport, thereby ensuring that siRNAs decrease BACE1 expression and modify relative pathways. Noticeably, Gal-NP@siBACE1 administration restored the deterioration of cognitive capacity in AD mice without notable side effects. This "Trojan horse" strategy supports the utility of RNA interference therapy in neurodegenerative diseases.