Cell Subtypes Within the Liver Microenvironment Differentially Interact with Lipid Nanoparticles

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.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.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.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.