Lipid nanoparticles (LNPs) have proven to be useful vesicles in the transportation of drugs and vaccines, like the SARS-CoV-2 vaccine. The particle size and structure of LNPs can change depending on the lipid composition and type of cargo, leading to a poor understanding of the structure of LNPs. Small angle neutron scattering (SANS) can be utilized to determine the structure and composition of multi-component systems, like LNPs. SANS takes advantage of the differences in the scattering length density (SLD) of hydrogen and deuterium to selectively highlight structural domains of LNPs by varying the solvent (H 2 O/D 2 O) ratio. Therefore, deuteration is important for the characterization of LNPs. We report the synthesis of deuterated ionizable lipid SM-102 (13 steps, 96% deuteration). Empty and RNA-loaded LNPs, composed of deuterated SM-102, deuterated DSPC, deuterated cholesterol, and DMG-PEG2000, are synthesized using a syringe pump and a microfluidic chip. Dynamic light scattering (DLS) and cryogenic electron microscopy (cryo-EM) are used to determine the particle size and uniformity. The LNP surface and internal structure are characterized by nuclear magnetic resonance (NMR) and SANS, respectively. This work provides insight into the spatial orientation of each lipid component and mRNA in LNPs.
Nusser et al. (Sun,) studied this question.