Structural transitions of ionizable cationic lipids in pH-sensitive liposomes using time-resolved synchrotron Small-Angle X-ray Scattering

In this project, structural transitions of pH-sensitive liposomes composed of ionizable cationic lipids are followed by Small-Angle X-ray Scattering (SAXS). Compared to the common anionic ionizable lipids, the cationic lipids offer higher interaction rate with negative bacterial membranes in acidic conditions. For cationic lipids, different mesophases and enhanced fusion are expected which would enable more efficient drug release. By SAXS at ID02, we can determine the lamellar structures at physiological pH, the dynamics of the proton-induced phase changes and the differences in the structures in acidic pH between formulations in ms time resolution. The formulations for this study are selected based on promising release profiles, TEM and DLS results. This study seeks to clarify the pH respond mechanisms of these liposomes, advancing the rational design of responsive lipid-nanocarriers and supporting the development of targeted antibiotic delivery strategies.

本研究采用小角X射线散射（Small-Angle X-ray Scattering, SAXS）技术，追踪由可电离阳离子脂质构成的pH敏感脂质体的结构转变过程。相较于常见的阴离子型可电离脂质，阳离子脂质在酸性环境下与阴性细菌细胞膜的结合速率更高。对于阳离子脂质而言，其有望呈现出不同的介晶相并具备更强的融合能力，从而实现更高效的药物释放。借助ID02线站的SAXS技术，我们能够以毫秒级时间分辨率，测定生理pH条件下的层状结构、质子诱导相变的动力学过程，以及不同制剂在酸性pH环境下的结构差异。本研究的制剂基于优异的药物释放曲线、透射电子显微镜（Transmission Electron Microscopy, TEM）与动态光散射（Dynamic Light Scattering, DLS）结果筛选得到。本研究旨在阐明这类脂质体的pH响应机制，推动响应型脂质纳米载体的合理化设计，并为靶向性抗生素递送策略的开发提供支撑。