Oxabispidine-derived ionizable lipids for effective mRNA delivery to the lungs using lipid nanoparticles

Lipid nanoparticles have been proven effective for mRNA delivery to the liver and in a vaccine context. There is general interest in identifying new ionizable lipids to enable safe and efficient mRNA delivery to a wider range of tissues and cells. A new series of ionizable lipids was developed using a conformationally constrained bicyclic diamine oxabispidine head group that shifts the apparent p<i>K</i>_a of nanoparticles to higher values relative to those reported as optimal for liver and vaccine delivery. By optimizing the lipid tail structure, we identified a lead lipid that efficiently encapsulated mRNA using the standard 4-component LNP formulation and showed potent and safe local delivery to the lungs in rats <i>via</i> the inhalation and intratracheal routes.