Martini 3 Building Blocks for Lipid Nanoparticle Design.

Area of Science:

• Biomolecular simulations
• Nanotechnology
• Drug delivery systems

Background:

• Lipid nanoparticles (LNPs) are crucial for drug and gene delivery but optimizing them is complex.
• Current experimental methods offer limited resolution and are costly.
• Atomic-level molecular dynamics (MD) simulations are computationally intensive.

Purpose of the Study:

• To enhance the understanding of lipid nanoparticle (LNP) technology through improved simulation models.
• To provide accurate and validated coarse-grained (CG) models for key LNP components.
• To develop practical tools for simulating and analyzing LNPs.

Main Methods:

• Extended the Martini 3 lipid library with over 100 new models, including ionizable lipids, sterols, and PEGylated lipids.
• Developed protocols for screening LNP fusion efficacy and constructing full LNPs.
• Utilized coarse-grained molecular dynamics (CG-MD) simulations.

Main Results:

• Introduced a comprehensive set of CG models for essential LNP components.
• Demonstrated the utility of the expanded library for simulating LNPs at CG resolution.
• Showcased protocols for analyzing LNP structure, dynamics, and fusion efficiency.

Conclusions:

• The expanded Martini 3 library provides a valuable toolset for CG-MD simulations of LNPs.
• The developed protocols facilitate the mechanistic understanding and optimization of LNP formulations.
• This work offers a scalable approach to advance LNP design and development.