Biomolecular simulations for the efficient design of lipid nanoparticles
- Principal Investigators:
- Prof. Nadine Schwierz-Neumann
- Project Manager:
- Nadine Schwierz-Neumann
- HPC Platform used:
- NHR@FAU: Fritz and Alex
- Project ID:
- b119ee
- Date published:
- Researchers:
- Akhil Sudarsan
- Introduction:
- Lipid nanoparticles (LNPs) are crucial for RNA delivery in gene therapies and vaccines. Our research investigates how LNPs respond to pH changes, with a focus on their structural transitions. By combining molecular dynamics simulations and X-ray scattering experiments, we gain detailed insights into the structural phase transitions between inverse lipid mesophases and explore how structural adaptability influences fusion and release efficiency. This integrated approach advances our molecular-level understanding of LNP dynamics, paving the way for designing more effective gene delivery systems.
- Body:
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Introduction
Lipid nanoparticles (LNPs) have become essential in the delivery of RNA-based therapeutics, including mRNA vaccines and gene therapies. Their effectiveness depends on their ability to remain stable in circulation and efficiently release genetic payloads within target cells. These processes are closely tied to the structural dynamics and phase transitions of LNPs, especially the shift to inverse hexagonal phases. However, experimental techniques often struggle to capture these molecular-level transitions in detail. To address this gap, we combine molecular dynamics simulations with experimental X-ray scattering. Simulations offer molecular-level insights, while experiments validate the models, creating a synergistic approach that enhances our understanding of LNP behavior.
Method
We used molecular dynamics simulations to explore the structural dynamics and phase transitions of ionizable lipid systems in response to pH changes. Our models incorporated ionizable lipids, helper lipids, and cholesterol from clinically relevant formulations. Protonation states of the ionizable lipids were adjusted to simulate the pH variations encountered during endosomal maturation. Accurate modeling of the ionizable lipid MC3 was achieved through parameterization based on quantum mechanical calculations, and validation by comparison with neutron reflectometry data. In addition, we established a methodology to correct for periodic image artefacts to provide quantitative comparison with high resolution X-ray scattering experiments.
Results
The simulations were designed to closely mimic the core phase of LNPs, comprising the ionizable lipid MC3, cholesterol, and water. Experimental X-ray scattering data revealed a clear pH-dependent phase transition from an inverse micellar phase at high pH to an inverse hexagonal phase at low pH. Our simulations accurately captured these transitions, and theoretical scattering profiles derived from the simulations showed excellent agreement with the experimental results. Moreover, the comparison of 2D electron density maps from simulations and experiments demonstrated quantitative agreement, highlighting the reliability of the simulations in capturing complex molecular-scale mechanisms. In summary, this combined approach provided critical insights into the behavior of LNPs, including molecular-level understanding of pH-dependent phase transitions.
References
Philipp, J. et al. pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function. Proc. Natl. Acad. Sci. USA 120, e2310491120 (2023). https://doi.org:10.1073/pnas.2310491120
- Institute / Institutes:
- Physics
- Affiliation:
- University of Augsburg
- Image:
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