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

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, AI; Xue, X; Shi, B

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

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, AI Xue, X Shi, B

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Publisher:: American Association for the Advancement of Science (AAAS)
Publication Type:: Journal Article
Citation:: Science advances, 2020, 6, (41)
Issue Date:: 2020-10-09

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Field	Value	Language
dc.contributor.author	Zhou, Y
dc.contributor.author	Zhu, F
dc.contributor.author	Liu, Y
dc.contributor.author	Zheng, M
dc.contributor.author	Wang, Y
dc.contributor.author	Zhang, D
dc.contributor.author	Anraku, Y
dc.contributor.author	Zou, Y
dc.contributor.author	Li, J
dc.contributor.author	Wu, H
dc.contributor.author	Pang, X
dc.contributor.author	Tao, W
dc.contributor.author	Shimoni, O https://orcid.org/0000-0001-8822-1024
dc.contributor.author	Bush, AI
dc.contributor.author	Xue, X
dc.contributor.author	Shi, B
dc.date.accessioned	2020-11-05T04:53:00Z
dc.date.available	2020-08-26
dc.date.available	2020-11-05T04:53:00Z
dc.date.issued	2020-10-09
dc.identifier.citation	Science advances, 2020, 6, (41)
dc.identifier.issn	2375-2548
dc.identifier.issn	2375-2548
dc.identifier.uri	http://hdl.handle.net/10453/143766
dc.description.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.
dc.format	Electronic-Print
dc.language	eng
dc.publisher	American Association for the Advancement of Science (AAAS)
dc.relation.ispartof	Science advances
dc.relation.isbasedon	10.1126/sciadv.abc7031
dc.rights	info:eu-repo/semantics/openAccess
dc.title	Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer's disease therapy.
dc.type	Journal Article
utslib.citation.volume	6
utslib.location.activity	United States
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - IBMD - Initiative for Biomedical Devices
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2020-11-05T04:52:52Z
pubs.issue	41
pubs.publication-status	Published
pubs.volume	6
utslib.citation.issue	41

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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http://hdl.handle.net/10453/143766