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Cholesterol in mRNA-Lipid Nanoparticles can be Replaced with the Synthetic Mycobacterial Monomycoloyl Glycerol Analogue MMG-1

Lokras, Abhijeet G. LU orcid ; Baghel, Saahil S. ; Jensen, Rune F. ; Thakur, Aneesh ; Franzyk, Henrik ; Thofte, Oskar LU orcid ; Herrera-Barrera, Marco ; Landry, Madeleine ; Ongun, Melike and Tami, Ahmad , et al. (2025) In Advanced Functional Materials
Abstract

Messenger RNA (mRNA) vaccines based on lipid nanoparticles (LNPs) are stabilized with cholesterol, which is thought to be a critical LNP component because it is essential for membrane integrity and endosomal escape. Here, it is shown that cholesterol in LNPs can be replaced with an immunopotentiating lipid, i.e., a synthetic analogue of the C-type lectin receptor agonist monomycoloyl glycerol (MMG-1), without compromising physicochemical properties, in vivo transfection efficiency, and immunogenicity of the mRNA-loaded LNPs (mRNA-LNPs). Replacement of cholesterol with MMG-1 results in LNPs that mediate intracellular delivery of mRNA, which is translated into high levels of protein in vivo. Replacement of cholesterol with MMG-1 in LNPs... (More)

Messenger RNA (mRNA) vaccines based on lipid nanoparticles (LNPs) are stabilized with cholesterol, which is thought to be a critical LNP component because it is essential for membrane integrity and endosomal escape. Here, it is shown that cholesterol in LNPs can be replaced with an immunopotentiating lipid, i.e., a synthetic analogue of the C-type lectin receptor agonist monomycoloyl glycerol (MMG-1), without compromising physicochemical properties, in vivo transfection efficiency, and immunogenicity of the mRNA-loaded LNPs (mRNA-LNPs). Replacement of cholesterol with MMG-1 results in LNPs that mediate intracellular delivery of mRNA, which is translated into high levels of protein in vivo. Replacement of cholesterol with MMG-1 in LNPs improves the transfection efficiency in T cells, B cells, and macrophages in the spleen and lymph nodes of mice. In mice, MMG-1-based LNPs loaded with mRNA encoding the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induce S-specific CD8+ T-cell responses and virus-neutralizing antibody responses, which are on par with the responses induced by cholesterol-based LNPs. Upon vaccination and a subsequent SARS-CoV-2 challenge of Syrian golden hamsters, replacement of cholesterol with MMG-1 in mRNA-LNPs enhances S-specific immunoglobulin G titers and reduces the SARS-CoV-2 load in the nasal cavity. These findings provide insights for improved design of LNPs for mRNA vaccine delivery.

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type
Contribution to journal
publication status
epub
subject
keywords
cholesterol, lipid nanoparticles, messenger RNA, monomycoloyl glycerol, SARS-CoV-2
in
Advanced Functional Materials
publisher
Wiley-Blackwell
external identifiers
  • scopus:105013225242
ISSN
1616-301X
DOI
10.1002/adfm.202505627
language
English
LU publication?
yes
id
0c9a2c0e-cd1b-4b3a-a392-df5f8b3483e9
date added to LUP
2025-11-20 10:06:42
date last changed
2025-11-20 10:08:01
@article{0c9a2c0e-cd1b-4b3a-a392-df5f8b3483e9,
  abstract     = {{<p>Messenger RNA (mRNA) vaccines based on lipid nanoparticles (LNPs) are stabilized with cholesterol, which is thought to be a critical LNP component because it is essential for membrane integrity and endosomal escape. Here, it is shown that cholesterol in LNPs can be replaced with an immunopotentiating lipid, i.e., a synthetic analogue of the C-type lectin receptor agonist monomycoloyl glycerol (MMG-1), without compromising physicochemical properties, in vivo transfection efficiency, and immunogenicity of the mRNA-loaded LNPs (mRNA-LNPs). Replacement of cholesterol with MMG-1 results in LNPs that mediate intracellular delivery of mRNA, which is translated into high levels of protein in vivo. Replacement of cholesterol with MMG-1 in LNPs improves the transfection efficiency in T cells, B cells, and macrophages in the spleen and lymph nodes of mice. In mice, MMG-1-based LNPs loaded with mRNA encoding the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induce S-specific CD8<sup>+</sup> T-cell responses and virus-neutralizing antibody responses, which are on par with the responses induced by cholesterol-based LNPs. Upon vaccination and a subsequent SARS-CoV-2 challenge of Syrian golden hamsters, replacement of cholesterol with MMG-1 in mRNA-LNPs enhances S-specific immunoglobulin G titers and reduces the SARS-CoV-2 load in the nasal cavity. These findings provide insights for improved design of LNPs for mRNA vaccine delivery.</p>}},
  author       = {{Lokras, Abhijeet G. and Baghel, Saahil S. and Jensen, Rune F. and Thakur, Aneesh and Franzyk, Henrik and Thofte, Oskar and Herrera-Barrera, Marco and Landry, Madeleine and Ongun, Melike and Tami, Ahmad and Thanthrige, Marlene P. and Callens, Eva and Beinat, Corinne and Rades, Thomas and Paludan, Søren R. and Riesbeck, Kristian and Rosenkrands, Ida and Christensen, Dennis and Pedersen, Gabriel K. and Foged, Camilla}},
  issn         = {{1616-301X}},
  keywords     = {{cholesterol; lipid nanoparticles; messenger RNA; monomycoloyl glycerol; SARS-CoV-2}},
  language     = {{eng}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Advanced Functional Materials}},
  title        = {{Cholesterol in mRNA-Lipid Nanoparticles can be Replaced with the Synthetic Mycobacterial Monomycoloyl Glycerol Analogue MMG-1}},
  url          = {{http://dx.doi.org/10.1002/adfm.202505627}},
  doi          = {{10.1002/adfm.202505627}},
  year         = {{2025}},
}