🧬 Excited to share our new work in @NatureBiotech! Paper: nature.com/articles/s41587-0… Research Briefing: nature.com/articles/s41587-0… Large gene editors require large mRNAs, but LNPs are typically discovered using much smaller reporter RNAs. We asked: does RNA size matter when discovering delivery lipids? Using a large base-editor mRNA for high-throughput screening, we identified LC-1, an ionizable lipid that enabled efficient gene editing in the liver, lung, and brain via different administration routes in mice, with up to 4× higher Cas9 editing than benchmark LNPs. LC-1 also efficiently delivered base editors for disease-relevant targets in hypercholesterolemia, cystic fibrosis, and Angelman syndrome. Why does LC-1 work so well? Cryo-EM and X-ray scattering revealed that LC-1 LNPs form an ordered, inverted-hexagonal structure that persists with large RNA cargo. This membrane-fusing structure helps RNA escape from endosomes, the compartments that can trap it inside cells. In cell studies, LC-1 released roughly twice as much large mRNA into the cytosol as the benchmark formulations. We show that LC-1's key design features also apply to ionizable lipids made through other synthetic routes. These findings show that accounting for RNA size from the start can change which lipids we discover and improve delivery of large gene editors. This could help expand the delivery options available for future gene-editing medicines. Thank you to all our co-authors, collaborators and funders @CIHR_IRSC @NSERC_CRSNG @UofTPharmacy @LisaDolovich @PMResearch_UHN @bradwouters #LipidNanoparticles #GeneEditing #RNATherapeutics