Advancing RNA Therapeutics: Molecular Dynamics Insights into Lipid Nanoparticle Design and Optimization for Enhanced Delivery

• Name: Advancing RNA Therapeutics: Molecular Dynamics Insights into Lipid Nanoparticle Design and Optimization for Enhanced Delivery , ModeLNP
• EuroHPC machine used: MareNostrum 5
• Topic: Health biotechnology

Overview of the project

The ModeLNP project focuses on understanding the molecular mechanisms that govern the structure, pH-dependent behavior, and endosomal escape of lipid nanoparticles (LNPs) used for siRNA delivery. Using a multi-resolution approach—coarse-grained, atomistic, and constant-pH molecular dynamics—the project investigated how ionizable lipid protonation, RNA–lipid interactions, and membrane fusion intermediates collectively determine LNP efficacy. The work bridges molecular-level simulations with experimental readouts and aims to identify design principles for next-generation RNA therapeutics.

How did EPICURE support the project and what were the benefits of the support?

The project primarily requested support for performance benchmarking, GPU optimisation, and installation of specialized software, particularly the GROMACS constant-pH MD (CpHMD) beta version, which is not available in standard system modules. The EPICURE team helped configure the software stack, ensured reproducible performance on MareNostrum5, and provided guidance on scaling behavior for atomistic simulations. This support was essential, as CpHMD simulations involve additional PME passes and require careful tuning to run efficiently on GPUs.

With the help from EPICURE, this project saved substantial time, reduced computational cost, and enabled simulations that would have otherwise been impractical to execute within the project timeline.