Molecular Dynamics Simulation of Lipid Nanoparticles Encapsulating mRNA.

Area of Science:

• Biochemistry
• Materials Science
• Pharmaceutical Sciences

Background:

• Messenger RNA (mRNA) vaccines are vital for infectious disease response.
• Lipid nanoparticles (LNPs) are essential delivery vehicles for mRNA vaccines, influencing their efficacy and stability.
• Understanding LNP encapsulation mechanisms is key to optimizing mRNA vaccine formulation.

Purpose of the Study:

• To investigate the self-assembly mechanisms of LNPs during mRNA encapsulation.
• To explore the impact of N/P ratios and acid types on LNP structure and properties.
• To elucidate the role of ionizable lipids in mRNA complexation within LNPs.

Main Methods:

• Molecular dynamics (MD) simulations were used to model LNP self-assembly.
• Ethanol solvent injection method was employed for LNP formation, mimicking experimental conditions.
• Analysis of LNP structure, component distribution, and interactions with mRNA under varying conditions (pH, N/P ratio).

Main Results:

• Lipid components self-assemble into nanoparticles, with SM-102 localizing in the core under neutral conditions.
• Acidic conditions trigger LNP disassembly and subsequent mRNA encapsulation by protonated SM-102 via electrostatic interactions and hydrogen bonds.
• LNPs exhibit a specific layered structure (DMG-PEG 2000, DSPC, cholesterol, SM-102) and optimal size/uniformity at low pH or low N/P ratios with citric acid.

Conclusions:

• The study clarifies the mechanism of mRNA encapsulation by LNPs, driven by electrostatic interactions under acidic conditions.
• Optimizing pH and N/P ratios, particularly with citric acid, can enhance LNP size and uniformity for improved mRNA vaccine delivery.
• Findings provide a foundation for designing advanced LNP formulations to boost mRNA vaccine efficacy.