Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, 92093-0358, USA.
Department of Chemistry and Biochemistry, San Diego State University, San Diego, California, 92182-1030, USA.
Sci Rep. 2019 Dec 18;9(1):19359. doi: 10.1038/s41598-019-55494-z.
A major challenge in liposomal research is to minimize the leakage of encapsulated cargo from either uncontrolled passive permeability across the liposomal membrane or upon fusion with other membranes. We previously showed that liposomes made from pure Archaea-inspired bipolar tetraether lipids exhibit exceptionally low permeability of encapsulated small molecules due to their capability to form more tightly packed membranes compared to typical monopolar lipids. Here, we demonstrate that liposomes made of synthetic bipolar tetraether lipids can also undergo membrane fusion, which is commonly accompanied by content leakage of liposomes when using typical bilayer-forming lipids. Importantly, we demonstrate calcium-mediated fusion events between liposome made of glycerolmonoalkyl glycerol tetraether lipids with phosphatidic acid headgroups (GMGTPA) occur without liposome content release, which contrasts with liposomes made of bilayer-forming EggPA lipids that displayed ~80% of content release under the same fusogenic conditions. NMR spectroscopy studies of a deuterated analog of GMGTPA lipids reveal the presence of multiple rigid and dynamic conformations, which provide evidence for the possibility of these lipids to form intermediate states typically associated with membrane fusion events. The results support that biomimetic GMGT lipids possess several attractive properties (e.g., low permeability and non-leaky fusion capability) for further development in liposome-based technologies.
脂质体研究中的一个主要挑战是最小化包裹货物从脂质体膜的不受控制的被动通透性或与其他膜融合时的泄漏。我们之前表明，由纯古菌启发的双极性四醚脂质制成的脂质体由于其形成更紧密堆积的膜的能力，与典型的单极脂质相比，表现出包裹小分子的异常低通透性。在这里，我们证明了由合成双极性四醚脂质制成的脂质体也可以进行膜融合，当使用典型的双层形成脂质时，这通常伴随着脂质体内容物的泄漏。重要的是，我们证明了具有磷酸酰基头部的甘油单烷基甘油四醚脂质（GMGTPA）制成的脂质体之间的钙介导融合事件不会发生脂质体内容物释放，这与在相同融合条件下显示出约 80%内容物释放的双层形成 EggPA 脂质制成的脂质体形成对比。GMGTPA 脂质的氘化类似物的 NMR 光谱研究揭示了存在多种刚性和动态构象，这为这些脂质形成与膜融合事件相关的中间状态的可能性提供了证据。结果表明，仿生 GMGT 脂质具有几种有吸引力的特性（例如，低通透性和无泄漏融合能力），可进一步开发基于脂质体的技术。
