How Lipid Types Affect the Structure of siRNA-Carrying Nanoparticles Revealed by Molecular-Level Analysis

Incorporating DSPC and cholesterol in ionizable lipid-based nanoparticles decreased the molecular mobility of ionizable lipids.

• DSPC reduced the overall molecular mobility of ionizable lipids, while cholesterol specifically decreased the mobility of their hydrophobic tails.
• The decreased molecular mobility and changed orientation of lipid mixtures helped maintain the stacked bilayer structure of siRNA and ionizable lipids.
• This structural maintenance contributed to increased siRNA encapsulation efficiency within the lipid nanoparticles.
• NMR relaxometry indicated that incorporating neutral lipids enhanced PEG chain flexibility at the interface of the nanoparticles.
• A small amount of DSPC improved PEG chain flexibility, which may enhance dispersion stability and lead to a narrower size distribution of the nanoparticles.
• Excess amounts of DSPC and cholesterol led to the formation of deformed particles and demixing of cholesterol within the nanoparticles.

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