  Lipid nanoparticles own a remarkable potential in nanomedicine, only
partially disclosed. While the clinical use of liposomes and cationic
lipid-nucleic acid complexes is well-established, liquid lipid nanoparticles
(nanoemulsions), solid lipid nanoparticles, and nanostructured lipid carriers
have even greater potential. However, they face obstacles in being used in
clinics due to a lack of understanding about the molecular mechanisms
controlling their drug loading and release, interactions with the biological
environment (such as the protein corona), and shelf-life stability. To create
effective drug delivery carriers and successfully translate bench research to
clinical settings, it is crucial to have a thorough understanding of the
internal structure of lipid nanoparticles. Through synchrotron small-angle
X-ray scattering experiments, we determined the spatial distribution and
internal structure of the nanoparticles' lipid, surfactant, and the water in
them. The nanoparticles themselves have a barrel-like shape that consists of
coplanar lipid platelets (specifically cetyl palmitate) that are partially
covered by polysorbate 80 surfactant and retain a small amount of hydration
water. Although the platelet structure was expected, the presence of surfactant
molecules forming sticky patches between adjacent platelets challenges the
classical 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 surrounding
water. These structural features play a significant role in drug loading and
release, biological fluid interaction, and nanoparticle stability, making these
findings valuable for the rational design of lipid-based nanoparticles.
