Molecular Drivers of Self-Assembly in RNA-Loaded lipid nanoparticles Revealed by Coarse-Grained simulations

Dec 3, 2025International journal of pharmaceutics

Molecular Factors Behind Self-Assembly of RNA-Carrying Lipid Nanoparticles Revealed by Simulations

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Abstract

Lipid nanoparticles (LNPs) formed larger, less ordered structures with increased ethanol content during RNA encapsulation.

LNPs are composed of various lipids, which spontaneously form complexes with mRNA when mixed with ethanol.
Non-polar forces dominate in the presence of a polar solvent, causing lipids to aggregate into spherical shapes.
Coulombic and hydrophilic interactions lead lipid aggregates to settle on the surface of mRNA until completely covering it.
Increased ethanol content influenced the behavior of phospholipids, causing them to migrate toward the inner region of LNPs.
A decrease in phospholipids on the LNP surface may reduce their ability to control particle aggregation.
Higher ethanol fractions are associated with the formation of larger nanoparticles that exhibit less order.

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The development of lipid nanoparticles (LNPs) has revolutionised RNA-based biopharmaceuticals, enabling efficient delivery of mRNA for therapeutic applications. LNPs consist of an ionisable lipid, a neutral phospholipid, cholesterol, and a PEG-ylated lipid (PL). The mixing of an aqueous solution containing mRNA with an ethanol solution containing the lipids leads to the spontaneous formation of mRNA-LNP complexes. However, the mechanisms underlying this process and the behaviour of each component under variable conditions remain partially unclear. Coarse-grained molecular dynamics was here employed to simulate the formation of RNA-loaded LNPs under various conditions, with a specific focus on ethanol. Following exposure to a polar solvent, non-polar forces prevailed, and lipids formed spherical aggregates. Due to Coulombic and hydrophilic interactions, aggregates settled on mRNA surface until they completely cover it. Finally, lipids rearranged depending on their affinity with the surrounding environment. The variation in the ethanol content did not affect the behaviour of lipids, except for the PL: when ethanol was added, the PL tended to migrate toward the inner region of the LNPs. The decrease in PLs on the external surface of LNPs could decrease their ability to regulate particle aggregation, leading to the formation of larger particles at higher ethanol content. Furthermore, higher ethanol fractions resulted in larger, less ordered nanoparticles. Together, these two phenomena could explain the experimental evidence of larger particle produced at higher ethanol content. These findings provide a detailed molecular understanding of LNP self-assembly, offering pivotal insights for designing more stable lipidic carriers for RNA encapsulation.

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Molecular Drivers of Self-Assembly in RNA-Loaded lipid nanoparticles Revealed by Coarse-Grained simulations

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