Lipid Nanoparticles (LNPs) are an attractive way of delivering of short interfering RNA (siRNA) for cancer therapeutics. Their release method relies on protonation of an ionisable amino-lipid (XTC2) in acidic endosomes. Hypothetically, the protonated XTC2 and anionic lipids in endosomal membranes interact to form non-lamellar phases, releasing the siRNA. In this project, a model release system consisting of XTC2 and anionic distearoylphosphatidylserine (DSPS-d70) at pH 4.7 was investigated with deuterium nuclear magnetic resonance (2H NMR) and small angle x-ray scattering (SAXS) to determine the lipid phases which form as a function of temperature and their structural parameters. Since cholesterol is an important structural component in LNPs, increasing amounts of cholesterol were added to the system to determine its effect. Non-lamellar phases were observed for each sample particularly at high-temperatures, though interestingly the specific phase observed by each technique was not always in complete agreement.
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