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

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    Author
    Zhou, Y; Zhu, F; Liu, Y; Zheng, M; Wang, Y; Zhang, D; Anraku, Y; Zou, Y; Li, J; Wu, H; ...
    Date
    2020-10-01
    Source Title
    Science Advances
    Publisher
    AMER ASSOC ADVANCEMENT SCIENCE
    University of Melbourne Author/s
    Bush, Ashley; Shimoni, Olga
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Zhou, 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 Status
    Open Access
    URI
    http://hdl.handle.net/11343/251684
    DOI
    10.1126/sciadv.abc7031
    Abstract
    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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