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Lipid nanoparticles own a remarkable potential in nanomedicine, onlypartially disclosed. While the clinical use of liposomes and cationiclipid-nucleic acid complexes is well-established, liquid lipid nanoparticles(nanoemulsions), solid lipid nanoparticles, and nanostructured lipid carriershave even greater potential. However, they face obstacles in being used inclinics due to a lack of understanding about the molecular mechanismscontrolling their drug loading and release, interactions with the biologicalenvironment (such as the protein corona), and shelf-life stability. To createeffective drug delivery carriers and successfully translate bench research toclinical settings, it is crucial to have a thorough understanding of theinternal structure of lipid nanoparticles. Through synchrotron small-angleX-ray scattering experiments, we determined the spatial distribution andinternal structure of the nanoparticles' lipid, surfactant, and the water inthem. The nanoparticles themselves have a barrel-like shape that consists ofcoplanar lipid platelets (specifically cetyl palmitate) that are partiallycovered by polysorbate 80 surfactant and retain a small amount of hydrationwater. Although the platelet structure was expected, the presence of surfactantmolecules forming sticky patches between adjacent platelets challenges theclassical core-shell model used to describe solid lipid nanoparticles.Additionally, the surfactant partially covers the water-nanoparticle interface,allowing certain lipid regions to come into direct contact with surroundingwater. These structural features play a significant role in drug loading andrelease, biological fluid interaction, and nanoparticle stability, making thesefindings valuable for the rational design of lipid-based nanoparticles.

Small-Angle X-ray Scattering Unveils the Internal Structure of Lipid Nanoparticles