Alternative Structural Lipids Impact mRNA-Lipid Nanoparticle Morphology, Stability, and Activity

Nov 26, 2025Molecular pharmaceutics

Different Lipids Change the Shape, Stability, and Function of mRNA Nanoparticles

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Abstract

Lipid nanoparticles with alternative structural lipids enhanced stability for over six months at refrigerated temperatures.

Different combinations of structural lipids produced various mesophases that affected the stability and quality of mRNA-containing lipid nanoparticles.
Hexagonal and cubic phase structures contributed to improved stability profiles for mRNA-LNPs under different temperature conditions.
Select mRNA-LNPs demonstrated varied activity in transfection and cytokine stimulation assays conducted in HeLa cells and whole human blood.
Reduced immunostimulatory cytokines were observed with certain novel mRNA-LNP formulations, indicating potential for less adverse immune responses.

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Lipid nanoparticles (LNPs) are critical drug delivery vehicles that enable functional mRNA delivery into cells to produce desired proteins, enabling vaccine and therapeutic applications. The structure and formulation of mRNA-containing LNPs (mRNA-LNPs) critically impact the delivery and protein production. Here, we generated LNPs with various structural lipids to improve the nanoparticle drug product stability and delivery profiles. We incorporated glyceryl monooleate and phytantriol as alternatives to traditional phospholipids (e.g., distearoylphosphatidylcholine). The physicochemical attributes of mRNA-LNPs were assessed by the hydrodynamic particle size, mRNA encapsulation, and mRNA integrity. mRNA-LNP morphology was assessed by synchrotron small-angle X-ray scattering, pulsed gradient stimulated echo proton nuclear magnetic resonance, and cryogenic-transmission electron microscopy.activity, including transfection and cytokine stimulation were evaluated in HeLa cells and whole human blood, respectively, for select mRNA-LNPs with varied morphologies. Alternative structural lipids in mRNA-LNPs produced different mesophases depending on the lipid type and molar ratio. Specific lipid combinations yielded distinct quality attributes and stability profiles, with uniqueactivities. Hexagonal and cubic phase structures enhanced mRNA-LNP stability at refrigerated and room temperatures for over six months and three months, respectively. These novel mRNA-LNPs provided promising benefits by reducing immunostimulatory cytokines, warranting further exploration. Our efforts demonstrate the nuances of LNP composition and its effects on structure, stability, and activity. In vitro in vitro

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Alternative Structural Lipids Impact mRNA-Lipid Nanoparticle Morphology, Stability, and Activity

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