Probing the Role of Lipid Nanoparticle Elasticity on mRNA Delivery to the Placenta.

It is well established that the physicochemical properties of lipid nanoparticles (LNPs) can govern their interactions with various biological barriers. One property hypothesized to influence nanoparticle-cell interactions is elasticity. Here, we formulate LNPs with naturally occurring cholesterol analogs to tune LNP elasticity and study its role on mRNA delivery to the placenta. LNP elasticity was measured via atomic force microscopy where these LNPs exhibited Young's moduli ranging from 71.0 ± 26.2 to 411.4 ± 145.7 kPa. In vitro screening of these LNPs in placental trophoblasts showed that stiffer LNPs improved LNP uptake and mRNA delivery compared with softer LNPs. Following intravenous administration to pregnant mice, the stiffer LNPs incorporating β-sitosterol enhanced placental and reduced liver mRNA delivery compared with softer LNPs containing only cholesterol. These results demonstrate the ability of stiffer LNPs to promote placental mRNA delivery and highlight the potential of tuning LNP elasticity to improve LNP-mediated mRNA delivery to organs of interest.