Discovery of a Novel Amino Lipid That Improves Lipid Nanoparticle Performance through Specific Interactions with mRNA

Lipid nanoparticles (LNPs) are capable of delivering messenger ribonucleic acid (mRNA) efficiently and systemically as a result of both particle composition and architecture. The particle architecture is determined by how the various components interact with one another to establish a stable equilibrium through self‐assembly. The Coulombic attraction between the anionic oligonucleotide cargo and the ionizable amino lipid within the encapsulation media contributes to the coalescence of the particles, but other interactions are also involved. Prior exploration of amino lipids for mRNA delivery via a traditional medicinal chemistry approach suggests that hydrogen bonding between a hydroxyl headgroup and the mRNA contributes to improved LNP in vivo expression. Herein, expansion of that work culminating in the discovery of a novel squaramide lipid that enables robust LNPs with high levels of expression is described. Molecular dynamics simulations and biophysical evidence both support the hypothesis that the squaramide is making specific interactions with mRNA resulting in particles with a more stable and efficient structure. A squaramide amino lipid that promotes specific interactions with mRNA and does not rely solely on ionic interactions for efficient complexation and assembly into lipid nanoparticles (LNPs) is described. Molecular dynamics simulations provide insight into which interactions may be responsible for the unique particle characteristics. This offers the exciting possibility that in silico lipid/mRNA modeling can improve LNP component design.