Coarse-Grained Simulations of RNA-Loaded Lipid Nanoparticles: Implications on RNA Stability and Antigenic Protein Expression in mRNA Vaccines

📖 Top 30% JournalSep 14, 2025The journal of physical chemistry. B

Simulations of RNA-Carrying Fat Nanoparticles and Their Impact on RNA Stability and Protein Production in mRNA Vaccines

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Abstract

Coarse-grained simulations indicate the strategic role of DLin-MC3-DMA (MC3) in lipid nanoparticles for RNA delivery across different pH levels.

Lipid nanoparticles (LNPs) are emerging as effective carriers for nucleic acid delivery, including mRNAs.
A specific class of molecules, ionizable lipids (ILs) like MC3, is critical for the stability and efficiency of mRNA delivery systems.
Simulations show that MC3 influences the structural organization and water content of LNPs.
The behavior of MC3 during endosomal fusion varies with pH, which may impact RNA release.
Selecting an appropriate IL is associated with challenges in designing effective RNA-LNP systems.

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Lipid nanoparticles (LNPs) have emerged across the pharmaceutical industry as a new category of promising vehicles to deliver a variety of therapeutics. In particular, these particles have great potential to deliver nucleic acids, including messenger RNAs (mRNAs), which have demonstrated their ability to be used as prophylactic and therapeutic drugs. In order to reach its target, an mRNA molecule requires a safe, effective, and stable delivery system that protects it from degradation, that allows cellular uptake, and the mRNA release in the cytoplasm. This is achieved in the commercial mRNA vaccines against COVID-19 by using a specific class of molecules called cationic lipids (CLs) or ionizable lipids (ILs) as one of the main components of the LNPs. In this article, we perform coarse-grained simulations using the Martini force field for large systems, encompassing all constituents of the LNP (RNA, IL, cholesterol, PEGylated lipids, and water), and we highlight the strategic role at different pHs of the DLin-MC3-DMA (MC3) molecule, which is commercially used as an RNA delivery vehicle. Then, we discuss the role of MC3 in the shaping, internal organization, and water content of the LNP. Finally, we investigate the role of MC3 as an IL during the endosomal fusion, and we describe its behavior at different pHs. Our results illustrate the challenges associated with the selection of an IL in the design of an RNA-LNP system, and IL's potential role in the RNA's stability and efficiency. This work can serve as a useful resource for the future development of new RNA-LNP carriers and mRNA-based vaccines. in vivo

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