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

doi:10.1126/sciadv.abc7031

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

Faculty of Medicine, Health and Human Sciences

Research output: Contribution to journal › Article › peer-review

207 Citations (Scopus)

86 Downloads (Pure)

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.

Original language	English
Article number	eabc7031
Pages (from-to)	1-14
Number of pages	14
Journal	Science Advances
Volume	6
Issue number	41
DOIs	https://doi.org/10.1126/sciadv.abc7031
Publication status	Published - 1 Oct 2020

Bibliographical note

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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10.1126/sciadv.abc7031Licence: CC BY-NC

Publisher version (open access)Final published version, 4.16 MBLicence: CC BY-NC

Cite this

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title = "Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer's disease therapy",

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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AU - Zhou, Yutong

AU - Zhu, Feiyan

AU - Liu, Yang

AU - Zheng, Meng

AU - Wang, Yibin

AU - Zhang, Dongya

AU - Anraku, Yasutaka

AU - Zou, Yan

AU - Li, Jia

AU - Wu, Haigang

AU - Pang, Xiaobin

AU - Tao, Wei

AU - Shimoni, Olga

AU - Bush, Ashley I.

AU - Xue, Xue

AU - Shi, Bingyang

N1 - 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.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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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Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer's disease therapy

Abstract

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New nanoparticle strategies for efficient delivery and controlled release into the brain

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

Abstract

Bibliographical note

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New nanoparticle strategies for efficient delivery and controlled release into the brain

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