Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer's disease therapy
AuthorZhou, Y; Zhu, F; Liu, Y; Zheng, M; Wang, Y; Zhang, D; Anraku, Y; Zou, Y; Li, J; Wu, H; ...
Source TitleScience Advances
PublisherAMER ASSOC ADVANCEMENT SCIENCE
AffiliationFlorey Department of Neuroscience and Mental Health
Document TypeJournal Article
CitationsZhou, Y., Zhu, F., Liu, Y., Zheng, M., Wang, Y., Zhang, D., Anraku, Y., Zou, Y., Li, J., Wu, H., Pang, X., Tao, W., Shimoni, O., Bush, A., Xue, X. & Shi, B. (2020). Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer's disease therapy. SCIENCE ADVANCES, 6 (41), https://doi.org/10.1126/sciadv.abc7031.
Access StatusOpen Access
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.
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