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Photo Mikael Lund

Mikael Lund

Professor

Photo Mikael Lund

Lipid shape and packing are key for optimal design of pH-sensitive mRNA lipid nanoparticles

Author

  • Giulio Tesei
  • Ya Wen Hsiao
  • Aleksandra Dabkowska
  • Gunnar Grõnberg
  • Marianna Yanez Arteta
  • David Ulkoski
  • David J. Bray
  • Martin Trulsson
  • Johan Ulander
  • Mikael Lund
  • Lennart Lindfors
Show all

Summary, in English

The ionizable-lipid component of RNA-containing nanoparticles controls the pH-dependent behavior necessary for an efficient delivery of the cargo - the so-called endosomal escape. However, it is still an empirical exercise to identify optimally performing lipids. Here, we study two well-known ionizable lipids, DLin-MC3-DMA and DLin-DMA using a combination of experiments, multiscale computer simulations, and electrostatic theory. All-atom molecular dynamics simulations, and experimentally measured polar headgroup pKavalues, are used to develop a coarse-grained representation of the lipids, which enables the investigation of the pH-dependent behavior of lipid nanoparticles (LNPs) through Monte Carlo simulations, in the absence and presence of RNA molecules. Our results show that the charge state of the lipids is determined by the interplay between lipid shape and headgroup chemistry, providing an explanation for the similar pH-dependent ionization state observed for lipids with headgroup pKa values about one-pH-unit apart. The pH dependence of lipid ionization is significantly influenced by the presence of RNA, whereby charge neutrality is achieved by imparting a finite and constant charge per lipid at intermediate pH values. The simulation results are experimentally supported by measurements of α-carbon 13C-NMR chemical shifts for eGFP mRNA LNPs of both DLin-MC3-DMA and DLin-DMA at various pH conditions. Further, we evaluate the applicability of a mean-field Poisson-Boltzmann theory to capture these phenomena.

Department/s

  • Computational Chemistry
  • eSSENCE: The e-Science Collaboration

Publishing year

2024

Language

English

Publication/Series

Proceedings of the National Academy of Sciences of the United States of America

Volume

121

Issue

2

Document type

Journal article

Publisher

National Academy of Sciences

Topic

  • Physical Chemistry (including Surface- and Colloid Chemistry)

Keywords

  • lipid ionization
  • lipid nanoparticle
  • pH controlled release
  • RNA encapsulation

Status

Published

ISBN/ISSN/Other

  • ISSN: 0027-8424