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

被引：174

作者：

Zhou, Yutong ^{[1
]}

Zhu, Feiyan ^{[2
]}

Liu, Yang ^{[2
,3
]}

Zheng, Meng ^{[2
]}

Wang, Yibin ^{[2
]}

Zhang, Dongya ^{[2
]}

Anraku, Yasutaka ^{[4
]}

Zou, Yan ^{[2
,5
]}

Li, Jia ^{[3
]}

Wu, Haigang ^{[2
]}

Pang, Xiaobin ^{[3
]}

Tao, Wei ^{[6
,7
]}

Shimoni, Olga ^{[8
]}

Bush, Ashley, I ^{[9
]}

Xue, Xue ^{[1
]}

Shi, Bingyang ^{[2
,5
]}

机构：

[1] Nankai Univ, Coll Pharm, State Key Lab Med Chem Biol, Tianjin 300350, Peoples R China

[2] Henan Univ, Henan Macquarie Uni Joint Ctr Biomed Innovat, Sch Life Sci, Kaifeng 475004, Henan, Peoples R China

[3] Henan Univ, Sch Pharm, Kaifeng 475004, Henan, Peoples R China

[4] Univ Tokyo, Grad Sch Engn, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan

[5] Macquarie Univ, Fac Med & Hlth Sci, Dept Biomed Sci, Sydney, NSW 2109, Australia

[6] Harvard Med Sch, Brigham & Womens Hosp, Ctr Nanomed, Boston, MA 02115 USA

[7] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA

[8] Univ Technol Sydney, Sch Math & Phys Sci, Inst Biomed Mat & Devices IBMD, 15 Broadway, Ultimo, NSW 2007, Australia

[9] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3010, Australia

来源：

SCIENCE ADVANCES | 2020年 / 6卷 / 41期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会; 中国国家自然科学基金;

关键词：

AMYLOID-PRECURSOR-PROTEIN; GLUCOSE TRANSPORTERS; NESTING-BEHAVIOR; DRUG DISCOVERY; BETA; DELIVERY; BACE1; TAU; PRESENILIN-1; INHIBITORS;

D O I：

10.1126/sciadv.abc7031

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Toxic aggregated amyloid-beta accumulation is a key pathogenic event in Alzheimer's disease (AD), which derives from amyloid precursor protein (APP) through sequential cleavage by BACE1 (beta-site APP cleavage enzyme 1) and gamma-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.

引用

页数：14

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