Lipid nanoparticles are successful at delivering genetic cargo to cells; however, only an estimated 2% of genetic information internalized into cells successfully escapes the endosome and can perform its intended function in the cytoplasm. Endosomal escape can occur via several mechanisms, including fusion of the LNP and the endosome to release cargo. It has been speculated that lipids with a positive Gaussian curvature modulus will be highly fusogenic. While the surface structure and composition of synthesized cubosomes undoubtedly influence fusion, it is difficult to systematically study the surface structure of dispersed 100 nm colloids with experimental methods. Coarse-grained molecular dynamics allows for complementary and systematic investigations on the surfaces of cubic phases: resolving 10–40 nm features, localizing compositions, and observing fusion events. First, the properties of the interface, when the structured bulk is truncated, are assessed. The truncated cubosomes cap themselves, closing off one water channel from the outer water phase, and have a relatively small characteristic length over which the interface affects bulk properties. The structure of diffuse interfaces is then investigated by allowing lipids to self-assemble atop capped supercells and by fusing bilayers with the cubosome surfaces. Resulting structures, local curvatures, and interfacial widths are analyzed and compared to existing models. Helper lipids (PEG-lipids, DOTAP, and cholesterol) are incorporated at varying distances from the surface to examine diffusion and equilibrium partitioning. The implications for fusogenic behavior and endosomal escape are discussed.
Tallman et al. (Sun,) studied this question.