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Atomistic Insights into Organization of RNA-Loaded Lipid Nanoparticles

  • Markéta Paloncýová*
    Markéta Paloncýová
    Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute (CATRIN), Palacký University Olomouc, Šlechtitelů 27, Olomouc 779 00, Czech Republic
    *Email: [email protected]
  • Martin Šrejber
    Martin Šrejber
    Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute (CATRIN), Palacký University Olomouc, Šlechtitelů 27, Olomouc 779 00, Czech Republic
  • Petra Čechová
    Petra Čechová
    Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute (CATRIN), Palacký University Olomouc, Šlechtitelů 27, Olomouc 779 00, Czech Republic
  • Petra Kührová
    Petra Kührová
    Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute (CATRIN), Palacký University Olomouc, Šlechtitelů 27, Olomouc 779 00, Czech Republic
  • Filip Zaoral
    Filip Zaoral
    IT4Innovations, VŠB − Technical University of Ostrava, 17. listopadu 2172/15, Ostrava-Poruba 708 00, Czech Republic
    More by Filip Zaoral
  • , and 
  • Michal Otyepka*
    Michal Otyepka
    Regional Centre of Advanced Technologies and Materials, Czech Advanced Technology and Research Institute (CATRIN), Palacký University Olomouc, Šlechtitelů 27, Olomouc 779 00, Czech Republic
    IT4Innovations, VŠB − Technical University of Ostrava, 17. listopadu 2172/15, Ostrava-Poruba 708 00, Czech Republic
    *Email: [email protected]
Cite this: J. Phys. Chem. B 2023, 127, 5, 1158–1166
Publication Date (Web):January 5, 2023
https://doi.org/10.1021/acs.jpcb.2c07671
Copyright © 2023 American Chemical Society

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    Abstract

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    RNA-based therapies have shown promise in a wide range of applications, from cancer therapy, treatment of inherited diseases to vaccination. Encapsulation of RNA into ionizable lipid (IL) containing lipid nanoparticles (LNPs) has enabled its safe and targeted delivery. We present here the simulations of the self-assembly process of pH-sensitive RNA-carrying LNPs and their internal morphology. At low pH, the simulations confirm a lipid core encapsulating RNA in the hexagonal phase. Our all-atom and coarse-grained simulations show that an RNA molecule inside an LNP is protected from interactions with ions by being enveloped in the charged ILs. At neutral pH, representing the environment after LNP administration into human tissues, LNPs expelled most of the encapsulated RNA and water and formed separate bulk IL-rich and ordered the helper-lipid-rich phase. Helper lipids arranged themselves to be in contact with RNA or water. The presented models provide atomistic understanding of the LNP structure and open a way to investigate them in silico, varying the LNP composition or interacting with other biostructures aiming at increasing the efficiency of RNA-based medicine.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpcb.2c07671.

    • Video of self-assembly in acidic conditions (MP4)

    • Changes in LNP morphology after deprotonation (MP4)

    • CG parameterization; detailed description of simulation protocol and analyses; simulation results; plots for all performed analyses on CG simulations; atomistic details into RNA–lipid interactions; final snapshots for all systems (Figures S24–S28); self-assembly simulation in all-atom resolution; hydrogen bonds analyses; AA simulation of IL deprotonation; characteristics of RNA; analyses of dengue virus RNA in LNP; and all additional data, figures, and references (PDF)

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    Cited By

    This article is cited by 1 publications.

    1. Amali G. Guruge, Dallas B. Warren, Colin W. Pouton, David K. Chalmers. Molecular Dynamics Simulation Studies of Bile, Bile Salts, Lipid-Based Drug Formulations, and mRNA–Lipid Nanoparticles: A Review. Molecular Pharmaceutics 2023, 20 (6) , 2781-2800. https://doi.org/10.1021/acs.molpharmaceut.3c00049

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