Investigating phase transitions in Lipid Nanoparticles (LNPs) by coupling SANS with in-situ DLS to aid LNP design

Lipid nanoparticles (also known as LNPs) are revolutionizing genetic medicine. Many clinical LNP formulations have surprisingly similar lipid compositions but different geometries. Recently, it has been reported that the buffers used to formulate LNPs impact LNP in vivo performance. We have used these findings to generate mRNA loaded LNPs with the same lipid composition but different internal structures.
A likely consequence of this is a redistribution of the lipid components which may alter the phase behavior and structural transitions of the LNPs. This experiment couples in-situ light scattering and SANS to study lipid nanoparticle structural variations, aggregation and stability over clinically relevant temperatures and spanning known phase transition regions. This will enable us to investigate which structural transitions LNPs undergo over these temperature ranges and correlate these to particle stability using in situ DLS. This information is critical for cell-based LNP assays where storage of LNPs between formulation and cell experiments is necessary and to enable enhanced shipment of LNPs. Furthermore we anticipate that establishing the structural changes during observed LNP phase transitions will enhance our ability to rationally engineer LNPs.