Introduction

Lipid nanoparticles (LNPs) tend to accumulate in the liver due to physiological factors. Whereas the biological mechanisms that promote LNP delivery to hepatocytes have been reported, the mechanisms that promote delivery to other cell types within the liver microenvironment are poorly understood. Single cell profiling studies have recently identified subsets of Kupffer cells and hepatic endothelial cells with distinct gene expression patterns and biological phenotypes; we hypothesized these subtypes would differentially interact with nanoparticles.

Methods

To test the hypothesis, we quantified nucleic acid (i) biodistribution and (ii) functional mRNA delivery within the liver microenvironment using two clinically relevant LNPs in vivo.

Results

We found that these LNPs distribute nucleic acids distribute to Kupffer cells and liver endothelial cells as efficiently as they distribute to hepatocytes, yet result in more functional mRNA delivery to endothelial cells. Additionally, we found these LNPs differentially accumulate in Kupffer and endothelial cell subsets.

Conclusions

These data suggest subsets of liver microenvironmental cells can differentially interact with nanoparticles in vivo, thereby altering LNP delivery. More generally, the data suggest that nucleic acid biodistribution is not sufficient to predict functional nucleic acid delivery in vivo.

中文翻译：

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肝脏微环境中的细胞亚型与脂质纳米颗粒有不同的相互作用。

介绍

由于生理因素，脂质纳米颗粒（LNP）倾向于在肝脏中积累。尽管已经报道了促进 LNP 递送至肝细胞的生物学机制，但促进递送至肝脏微环境内其他细胞类型的机制却知之甚少。单细胞分析研究最近发现了具有不同基因表达模式和生物学表型的枯否细胞亚群和肝内皮细胞。我们假设这些亚型会与纳米粒子发生不同的相互作用。

方法

为了检验这一假设，我们使用体内两种临床相关的 LNP 对肝脏微环境内的核酸 (i) 生物分布和 (ii) 功能性 mRNA 递送进行了量化。

结果

我们发现这些 LNP 将核酸分配给枯否细胞和肝内皮细胞的效率与它们分配给肝细胞的效率一样，但会导致更多功能性的 mRNA 递送至内皮细胞。此外，我们发现这些 LNP 在 Kupffer 和内皮细胞亚群中存在差异性积累。

结论

这些数据表明，肝脏微环境细胞的亚群可以在体内与纳米颗粒进行不同的相互作用，从而改变 LNP 的传递。更一般地，数据表明核酸生物分布不足以预测体内功能性核酸递送。