Engineering lipid nanoparticle surface hydrophobicity to modulate nano-bio interface and enable tissue-selective mRNA delivery.

Predominant liver accumulation remains a major challenge for the application of lipid nanoparticle (LNP)-based gene therapies. While tuning the apparent pKa is an effective strategy for influencing endogenous proteins that regulate LNP-mediated tissue-specific delivery, recent evidence suggests that alternative mechanisms may exist. Here, we reveal a new mechanism by which LNP surface hydrophobicity influences extrahepatic delivery. Using dendrimers as modular molecules and an in-house developed surface hydrophobicity assay, we show that reducing lipid grafting on the dendrimer decreases the surface hydrophobicity of dendrimer-based LNPs (dLNPs), leading to reduced stability in plasma and decreased plasma protein adsorption. This diminishes the ability of LNPs to target liver hepatocytes through endogenous mechanisms involving interactions between apolipoproteins and their cognate receptors. At the same time, we find that dLNPs with lower surface hydrophobicity exhibit enhanced targeting of granulocytes relative to monocytic cells, potentially due to complement protein interactions. Further modification of dendrimers with quaternary amines increases dLNP surface charge density and improves lung delivery by preferentially targeting lung epithelial cells. While this modification also reduces surface hydrophobicity, the enhanced lung delivery is associated with distinct protein corona compositions rather than reduced protein adsorption. These findings establish modulation of LNP surface hydrophobicity as a novel strategy for achieving extrahepatic delivery.