Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles

Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for small interfering RNA delivery, there still challenges to use this formulation delivery. LNPs typically a mixture cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and PEG-lipid. The structural characterization mRNA-containing (mRNA-LNPs) is crucial full understanding way which they function, but information alone not enough predict their fate upon entering bloodstream. biodistribution cellular uptake affected surface composition as well extracellular present at site LNP administration, e.g., apolipoproteinE (ApoE). ApoE, being responsible fat transport body, plays key role LNP’s plasma circulation time. In work, we small-angle neutron scattering, together with selective solvent deuteration, elucidate structure distribution components absence presence ApoE. DSPC cholesterol found be enriched buffer, binding ApoE induces redistribution lipids shell core, also impacts internal structure, causing release mRNA. rearrangement incubation discussed terms potential relevance endosomal escape.