Abstract
The pH-dependent change in protonation of ionizable lipids is crucial for the success of lipid-based nanoparticles as mRNA delivery systems. Despite their widespread application in vaccines, the structural changes upon acidification are not well understood. Molecular dynamics simulations support structure prediction but require an a-priori knowledge of the lipid packing and protonation degree. The presetting of the protonation degree is a challenging task in the case of ionizable lipids since it depends on pH and on the local lipid environment and often lacks experimental validation. Here, we introduce a methodology of combining all-atom molecular dynamics simulations with experimental total-reflection X-ray fluorescence and scattering measurements for the ionizable lipid Dlin-MC3-DMA (MC3) in POPC monolayers. This joint approach allows us to simultaneously determine the lipid packing and the protonation degree of MC3. The consistent parameterization is expected to be useful for further predictive modeling of the action of MC3-based lipid nanoparticles.
Publisher
Cold Spring Harbor Laboratory
Reference61 articles.
1. Z. Li , J. Carter , L. Santos , C. Webster , C. F. van der Walle , P. Li , S. E. Rogers , and J. R. Lu , “Acidification-induced structure evolution of lipid nanoparticles correlates with their in vitro gene transfections,” ACS nano (2023).
2. “Lipid nanoparticles for mrna delivery;Nature Reviews Materials,2021
3. “mrna vaccine for cancer immunotherapy;Molecular Cancer,2021
4. “Ionization and structural properties of mrna lipid nanoparticles influence expression in intramuscular and intravascular administration;Communications biology,2021
5. “Maximizing the potency of sirna lipid nanoparticles for hepatic gene silencing in vivo;Angewandte Chemie,2012