Molecular Dynamics of Lipid Nanoparticles Explored through Solution and Solid-State NMR Spectroscopy and MD
Ryan Schroder1, Umut Ozuguzel2, Yong Du1
1Analytical Research & Development, Merck & Co., Inc, Rahway, New Jersey 07065, United States.
The Journal of Physical Chemistry. B
|June 11, 2025
Summary
Lipid nanoparticles (LNPs) dynamics were studied using NMR and simulations. siRNA encapsulation impacts cationic lipid mobility, suggesting a dense core, while the outer membrane dynamics are influenced by PEGylated lipids and temperature.
Area of Science:
- Biophysics
- Materials Science
- Drug Delivery
Background:
- Lipid nanoparticles (LNPs) are essential for nucleic acid delivery.
- Understanding LNP structure-dynamics is key for therapeutic efficacy.
Purpose of the Study:
- To investigate lipid dynamics in siRNA-loaded LNPs across a wide temperature range.
- To elucidate the roles of different lipid components and siRNA encapsulation on LNP stability.
Main Methods:
- Integrated solution and solid-state Nuclear Magnetic Resonance (NMR) spectroscopy.
- Molecular Dynamics (MD) simulations.
- 1H-13C cross-polarization (CP) and insensitive nuclei enhanced by polarization transfer (INEPT) NMR experiments.
- Relaxation-filtered Diffusion-Ordered NMR Spectroscopy (DOSY).
Main Results:
- Cationic lipid (Lipid X) shows high nanosecond dynamics, reduced by siRNA encapsulation, supporting a dense core model.
- Outer membrane lipids (DSPC, cholesterol) exhibit slower dynamics than the cationic lipid.
- PEGylated lipids influence surface dynamics; phase transitions observed at -20 °C (membrane) and -50 °C (core).
Conclusions:
- siRNA encapsulation and temperature significantly affect LNP lipid dynamics and stability.
- Findings provide molecular insights into LNP core-surface interactions.
- Guidance for developing more stable and effective LNP formulations for therapeutics.
