载脂蛋白E
低密度脂蛋白受体
基因敲除
向性
小干扰RNA
核糖核酸
受体
生物
细胞生物学
基因传递
载脂蛋白B
RNA干扰
脂蛋白
计算生物学
基因
遗传学
遗传增强
胆固醇
生物化学
医学
病理
病毒
疾病
作者
Alejandro J. Da Silva Sanchez,Curtis Dobrowolski,Ana Cristian,Elisa Schrader Echeverri,Kun Zhao,Marine Z. C. Hatit,David Loughrey,Kalina Paunovska,James E. Dahlman
出处
期刊:Nano Letters
[American Chemical Society]
日期:2022-06-07
卷期号:22 (12): 4822-4830
被引量:28
标识
DOI:10.1021/acs.nanolett.2c01133
摘要
To predict whether preclinical lipid nanoparticle (LNP) delivery will translate in humans, it is necessary to understand whether the mechanism used by LNPs to enter cells is conserved across species. In mice, non-human primates, and humans, LNPs deliver RNA to hepatocytes by adsorbing apolipoprotein E (ApoE), which binds low-density lipoprotein receptor (LDLR). A growing number of LNPs can deliver RNA to nonhepatocytes, suggesting that ApoE- and LDLR-independent interactions could affect LNP tropism. To evaluate this hypothesis, we developed a universal DNA barcoding system that quantifies how chemically distinct LNPs deliver small interfering RNA in any mouse model, including genetic knockouts. We quantified how 98 different LNPs targeted 11 cell types in wildtype, LDLR–/–, very low-density lipoprotein receptor, and ApoE–/– mice, studying how these genes, which traffic endogenous lipids, affected LNP delivery. These data identified a novel, stereopure LNP that targets Kupffer cells, endothelial cells, and hepatocytes in an ApoE-independent manner. These results suggest that non-ApoE interactions can affect the tropism of LNP-RNA drugs.
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