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

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 I. Bush, Xue Xue, Bingyang Shi

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)
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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.

Original languageEnglish
Article numbereabc7031
Pages (from-to)1-14
Number of pages14
JournalScience Advances
Issue number41
Publication statusPublished - 1 Oct 2020

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Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


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