First Contact: Lipid Nanoparticles Orient and Restructure at Interfaces

Lipid nanoparticles (LNPs) enable nanocarriers for nucleic acid delivery, often incorporating nonlamellar mesophases linked to membrane fusion, yet their structural evolution at biological interfaces remains unresolved.Using in-situ grazing-incidence small-angle X-ray scattering (GISAXS), we capture the interfacial cross-sections of LNPs prior to and during membrane interactions.Inverse cubic nanoparticles adopt preferred orientations such that water channels run parallel and normal to the substrate, while inverse hexagonal nanoparticles lie flat with channels aligned along the surface.Notably, upon contact with membrane mimics, the fusion intermediates reveal interface-restructuring pathways toward inverse mesophase topologies regardless of the initial LNP type, including cubosomes, hexosomes, and clinical COVID-19 vaccine LNPs.The interfacial mesophase restructuring emerges as a structural feature underlying LNP function and provides a framework for engineering interface-responsive nanocarriers.