Alzheimer`s disease (AD) is the most common age-related neurodegenerative disorder, characterized by progressive deterioration of cognitive capacity. 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 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 blood brain barrier (BBB) via glycemia-controlled glucose transporter-1 (Glut1) mediated transport, thereby ensuring siRNAs decrease BACE1 expression and amyloid plaques, suppress phosphorylated tau protein production, and promote myelin regeneration. Noticeably, Gal-NP@siBACE1 administration restored the deterioration of cognitive capacity in AD mice without significant side-effects. This novel “Trojan horse” strategy to deliver siRNA through BBB supports the utility of RNA interference therapy in neurodegenerative diseases.

Ph.D candidate Zhu Feiyan and Dr. Liu Yang are the co-first authors of the paper. Prof. Zheng Meng, Prof. Shi Bingyang and Prof. Xue Xue are the co-corresponding authors of the paper.

This work has been supported by Henan University and Macquarie University. Researchers from University of Tokyo(JPN), Nankai University(CHN), Macquarie University(AUS), University of Melbourne(AUS), University of Technology Sydney(AUS) and Harvard Medical School(US) participated in this study.

Paper link: http://bs.henu.edu.cn/info/1141/2252.htm

DOI: 10.1126/sciadv.abc7031