Thermodynamic Model and Experiments Indicate Kinetically Trapped States in Ionisable Lipid Nanoparticles

Geometric frustration from packing constraints is linked to mesophase stability in ionisable lipid nanoparticles, with a continuum model parameterized using MC3 and ALC-0315 data.

• Why it matters: A quantitative framework connecting molecular lipid properties to pH-dependent mesophase transitions—and thus LNP function and endosomal escape—is still missing.
• What they did: The study combined SAXS, Laurdan fluorescence, all-atom molecular dynamics, and continuum modeling to map pH- and temperature-dependent LII–HII transitions in bulk lipids and LNPs with MC3 or ALC-0315.
• The result: Laurdan tracked the same pH/temperature transitions as SAXS in both bulk and LNP systems, enabling a parameterized continuum theory that suggests kinetically trapped, metastable core states after pH changes.

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