Research Division Integrated Bioprocess Development, Institute of Chemical, Environmental and Bioscience Engineering, TU Wien, Gumpendorfer Straße 1a, Vienna 1060, Austria.
Research Division Organic & Biological Chemistry, Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163, Vienna 1060, Austria.
Eur J Pharm Biopharm. 2024 Apr;197:114213. doi: 10.1016/j.ejpb.2024.114213. Epub 2024 Feb 10.
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.
中性和正电荷的古菌醚脂（AEL）已被研究用作新型 pDNA 传递系统，在缺乏明显毒性的情况下，显示出高效的免疫反应和强烈的记忆效应。最近的技术进步使 mRNA 脂质纳米粒（LNPs）成为下一代传递系统的前沿；然而，目前还没有研究检查 AEL 在 mRNA 传递中的应用。在这项研究中，我们研究了来自嗜酸热硫化叶菌的粗脂质提取物或纯化的四醚脂质 caldarchaeol，作为 mRNA LNPs 的潜在新型赋形剂。根据它们在各自 LNP 中的摩尔份额，与一种知名的参考制剂相比，在使用原代细胞来源（HSMM）和已建立的细胞系（Caco-2、C2C12）的体外转染实验中，颗粒摄取和 mRNA 表达水平可提高多达 10 倍。这种效率的提高可能与内体逃逸的显著影响有关，表明 AEL 具有融合和溶血性特征。这项研究显示了古菌醚脂在 mRNA 传递中的高价值，并为未来的体内实验和进一步研究提供了坚实的基础。
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