Department of Physics, Johannes Gutenberg University Mainz, Staudingerweg 9, Mainz 55128, Germany.
Faculty of Physics and Astronomy, Ruhr University Bochum, Universitätsstrasse 150, Bochum 44801, Germany.
J Phys Chem B. 2024 Oct 17;128(41):10165-10177. doi: 10.1021/acs.jpcb.4c05057. Epub 2024 Oct 4.
Lipid-based nanomaterials are used as a common delivery vehicle for RNA therapeutics. They typically include a formulation containing ionizable cationic lipids, cholesterol, phospholipids, and a small molar fraction of PEGylated lipids. The ionizable cationic lipids are considered a crucial element of the formulation for the way they mediate interactions with the anionic RNA as a function of pH. Here, we show, by means of molecular dynamics simulation of lipid formulations containing two different ionizable cationic lipids (DLinDMA and DLinDAP), that the direct interactions of those lipids with RNA, taken alone, may not be sufficient to determine the level of protection and packaging of mRNA. Our simulations help and highlight how the collective behavior of the lipids in the formulation, which determines the ability to envelop the RNA, and the level of hydration of the lipid-RNA interface may also play a significant role. This allows the drawing of a hypothesis about the experimentally observed differences in the transfection efficiency of the two ionizable cationic lipids.
基于脂质的纳米材料被用作 RNA 治疗药物的常见递送载体。它们通常包含一种制剂，其中含有可离子化的阳离子脂质、胆固醇、磷脂和一小部分 PEG 化脂质。可离子化的阳离子脂质被认为是该制剂的一个关键要素，因为它们可以根据 pH 值调节与阴离子 RNA 的相互作用。在这里，我们通过含有两种不同可离子化阳离子脂质（DLinDMA 和 DLinDAP）的脂质制剂的分子动力学模拟表明，这些脂质与 RNA 的直接相互作用本身可能不足以确定 mRNA 的保护和包装水平。我们的模拟有助于突出和强调制剂中脂质的集体行为如何决定 envelop RNA 的能力以及脂质-RNA 界面的水合程度也可能发挥重要作用。这使得我们可以对两种可离子化阳离子脂质的转染效率的实验观察到的差异提出假设。
