Journal Article

PUBDB-2025-04818

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Combining SAXS analysis and MD simulation to determine structure and hydration of ionizable lipid hexagonal phases

Philipp, J.Extern*EMBL* ; Sudarsan, A. ; Kostyurina, E. ; Meklesh, V. ; Berglund, M. ; Rappolt, M. ; Westergren, J. ; Lindfors, L. ; Schwierz, N. ; Rädler, J. O. (Corresponding author)Extern*EMBL*

2025
Royal Soc. of Chemistry London

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Please use a persistent id in citations: doi:10.1039/D5SM00666J  doi:10.3204/PUBDB-2025-04818

Abstract: Cationic ionizable lipids (CILs) are fundamental components of inverse hexagonal (HII) lipid assemblies, which mediate the encapsulation and release of negatively charged mRNA through a pH-dependent mechanism. Since variations in the structure and composition of the HII phases can significantly impact the biological efficacy of the mRNA-carrying lipid nanoparticles (LNP), a comprehensive understanding of the ionizable lipid HII phases is necessary. We present an integrated approach combining small-angle X-ray scattering (SAXS) experiments, molecular dynamics (MD) simulations and a continuum model to elucidate lipid distribution and water content within HII phases. Our results indicate strong agreement between structures derived from MD simulations and SAXS data. To this end, we introduce a method to correct for periodic boundary artifacts when computing scattering profiles from MD simulations. This enables direct, model-free comparisons between experimental and simulated data, enhancing the reliability of structural interpretations, specifically the water content of the HII phases. Next, we developed a continuum model to extend structural analysis to CIL HII phases for which MD data is unavailable. This integrative framework not only provides molecular-level insights into the ionizable lipid HII mesophase but also enables the prediction of hydration properties across different CIL compositions. The different approaches consistently yield water contents that seem to correlate with the lipids’ transfection efficiencies. By bridging experimental and simulation data, our approach offers a powerful tool for the rational design and optimization of lipid nanoparticles, potentially linking a lower water content with an increased therapeutic performance.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project G:(GEPRIS)440719683 - Hochleistungscompute-Cluster (440719683) (440719683)
3. SINE2020 - World class Science and Innovation with Neutrons in Europe 2020 – SINE2020 (654000) (654000)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)
2. PETRA Beamline P62 (PETRA III)

Appears in the scientific report 2025

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Essential Science Indicators ; IF < 5 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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