Direct visualization of the structural transformation between the lyotropic liquid crystalline lamellar and bicontinuous cubic mesophase

The transition between the lyotropic liquid crystalline lamellar and the bicontinuous cubic mesophase drives multiple fundamental cellular processes involving changes in cell membrane topology, including endocytosis and membrane budding. While several theoretical models have been proposed to explain this dynamic transformation, experimental validation of these models has been challenging because of the short-lived nature of the intermediates present during the phase transition. Herein, we report the direct observation of a lamellar-to-bicontinuous cubic phase transition in nanoscale dispersions using a combination of cryogenic transmission electron microscopy and static small-angle X-ray scattering. The results represent the first experimental confirmation of a theoretical model which proposed that the bicontinuous cubic phase originates from the center of a lamellar vesicle then propagates outward via the formation of interlamellar attachments and stalks. The observation was possible because of the precise control of the lipid composition to place the dispersion systems at the phase boundary of a lamellar and a cubic phase, allowing for the creation of long-lived structural intermediates. By the surveying of the nanoparticles using cryogenic transmission electron microscopy, a complete phase transition sequence was established.