Archaeal ether lipids improve internalization and transfection with mRNA lipid nanoparticles.

Neutral and positively charged archaeal ether lipids (AEL) have been studied for their utilization as novel delivery systems for pDNA, showing efficient immune response with a strong memory effect while lacking noticeable toxicity. Recent technological advances placed mRNA lipid nanoparticles (LNPs) at the forefront of next-generation delivery systems; however, no study has examined AELs in mRNA delivery yet. In this study, we investigated either a crude lipid extract or the purified tetraether lipid caldarchaeol from Sulfolobus acidocaldarius as potential novel excipients for mRNA LNPs. Depending on their molar share in the respective LNP, particle uptake, and mRNA expression levels could be increased by up to 10-fold in in vitro transfection experiments using both primary cell sources (HSMM) and established cell lines (Caco-2, C2C12) compared to a well-known reference formulation. This increased efficiency might be linked to a substantial effect on endosomal escape, indicating fusogenic and lyotropic features of AELs. This study shows the high value of archaeal ether lipids for mRNA delivery and provides a solid foundation for future in vivo experiments and further research. Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Citation

Viktor Laurin Sedlmayr, Silvia Schobesberger, Sarah Spitz, Peter Ertl, David Johannes Wurm, Julian Quehenberger, Oliver Spadiut. Archaeal ether lipids improve internalization and transfection with mRNA lipid nanoparticles. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2024 Apr;197:114213

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PMID: 38346479

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