Universal Barcoding Predicts In Vivo ApoE-Independent Lipid Nanoparticle Delivery.
Universal Barcoding Predicts In Vivo ApoE-Independent Lipid Nanoparticle Delivery.
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通用条形码预测体内不依赖于 ApoE 的脂质纳米粒子递送。
DOI：
10.1021/acs.nanolett.2c01133
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发表时间：
2022
期刊：
影响因子：
10.8
通讯作者：
J. Dahlman
中科院分区：
文献类型：
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作者：
Alejandro Da Silva Sanchez;C. Dobrowolski;A. Cristian;Elisa Schrader Echeverri;Kun Zhao;Marine Z. C. Hatit;David Loughrey;Kalina Paunovska;J. Dahlman
为了预测临床前脂质纳米颗粒（LNP）递送是否会在人类中翻译，有必要了解LNP进入细胞的机制是否在物种间是保守的。在小鼠、非人灵长类动物和人类中，LNPs通过吸附载脂蛋白E （ApoE）将RNA传递到肝细胞，载脂蛋白E与低密度脂蛋白受体（LDLR）结合。越来越多的LNPs可以将RNA传递到非肝细胞，这表明ApoE-和ldlr -独立的相互作用可能影响LNP的趋向性。为了评估这一假设，我们开发了一个通用的DNA条形码系统，该系统量化了化学上不同的LNPs如何在任何小鼠模型中传递小干扰RNA，包括基因敲除。我们量化了98种不同LNPs如何靶向野生型、LDLR-/-型、极低密度脂蛋白受体和ApoE-/-型小鼠中的11种细胞类型，研究了这些运输内源性脂质的基因如何影响LNP的传递。这些数据确定了一种新的、立体的LNP，它以不依赖apoe的方式靶向Kupffer细胞、内皮细胞和肝细胞。这些结果表明，非apoe相互作用可以影响LNP-RNA药物的趋向性。
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.