Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
Department of Chemical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
Nano Lett. 2022 Jun 22;22(12):4822-4830. doi: 10.1021/acs.nanolett.2c01133. Epub 2022 Jun 7.
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.
为了预测临床前脂质纳米颗粒（LNP）递药是否能在人体中转化，有必要了解 LNP 进入细胞所采用的机制在物种间是否保守。在小鼠、非人灵长类动物和人类中，LNP 通过吸附载脂蛋白 E（ApoE），结合低密度脂蛋白受体（LDLR），将 RNA 递送至肝细胞。越来越多的 LNP 可将 RNA 递送至非肝细胞，这表明 ApoE 和 LDLR 非依赖性相互作用可能影响 LNP 的趋向性。为了评估这一假说，我们开发了一种通用的 DNA 条形码系统，该系统可定量评估化学性质不同的 LNP 在任何小鼠模型（包括基因敲除小鼠）中递送小干扰 RNA 的情况。我们量化了 98 种不同的 LNP 靶向野生型、LDLR、极低密度脂蛋白受体和 ApoE 小鼠的 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 的递药。这些数据确定了一种新型、立体专一的 LNP，可通过非 ApoE 依赖性方式靶向库普弗细胞、内皮细胞和肝细胞。这些结果表明，非 ApoE 相互作用可影响 LNP-RNA 药物的趋向性。
