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

• Published in: Science Advances Vol. 6; no. 41
• Main Authors: Zhou, Yutong, Zhu, Feiyan, Liu, Yang, Zheng, Meng, Wang, Yibin, Zhang, Dongya, Anraku, Yasutaka, Zou, Yan, Li, Jia, Wu, Haigang, Pang, Xiaobin, Tao, Wei, Shimoni, Olga, Bush, Ashley I., Xue, Xue, Shi, Bingyang
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 09.10.2020; American Association for the Advancement of Science
• Subjects: Alzheimer Disease; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - therapy; Amyloid beta-Protein Precursor; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Blood-Brain Barrier; Blood-Brain Barrier - metabolism; Health and Medicine; Mice; Mice, Transgenic; Nanomedicine; Neuroscience; RNA, Small Interfering; RNA, Small Interfering - genetics; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abc7031

Glycosylated “triple-interaction” stabilized siRNA nanomedicine ameliorated AD neuropathology by targeting BACE1. 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.