Key Findings
The study establishes a quantitative continuum theory for pH-dependent mesophase transitions in ionisable lipid nanoparticles (LNPs), specifically identifying the existence of kinetically trapped metastable states in the LNP core phase in response to pH changes. By combining experimental data with theoretical analysis, the researchers determined that geometric frustration resulting from packing constraints is a primary determinant of mesophase stability.
Technical Details
The research utilized a combination of small-angle X-ray scattering (SAXS), Laurdan fluorescence spectroscopy, all-atom molecular dynamics simulations, and continuum modeling to analyze LNPs containing the ionisable lipids MC3 or ALC-0315. Key technical results include:
- Laurdan fluorescence measurements were found to report the same pH- and temperature-dependent transitions in both bulk lipid systems and LNPs.
- These transitions closely follow the inverse micellar (L II) to inverse hexagonal (H II) transitions identified via SAXS.
- The researchers parameterized a continuum model of the L II – H II transition to provide a quantitative description of stability.
- The analysis determined relevant membrane parameters, including Gaussian curvature bending rigidities and mean curvature bending rigidities, to identify the parameter ranges governing phase stability.
Background & Context
LNPs are currently the primary delivery vehicles for RNA-based therapies. It has been proposed that pH-dependent mesophase transitions of ionisable lipids are crucial for LNP function and the process of endosomal escape. However, until this study, a consistent quantitative framework linking the thermodynamics of these transitions to molecular lipid properties was lacking.
Significance & Outlook
By providing a quantitative link between molecular properties and mesophase thermodynamics, this framework allows for a deeper understanding of how LNP cores behave under varying pH and temperature conditions. The identification of metastable states as an inherent feature of the LNP core phase provides a theoretical basis for optimizing the delivery efficiency of RNA-based therapeutics.
Source: https://www.biorxiv.org/content/10.64898/2026.10.28.762589v1
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