Self-assembled nanocomplexes comprising biomolecules and lipid vesicles have been attracted great attention because of their high potential as efficient nanocarriers for gene delivery and bioimaging applications. Most studies have focused on the cationic lipid-DNA complexes, so called lipoplexes, although proteins that exhibit opposite charge to the lipid could also form nanocomplexes. The protein-lipid complexes could have distinctive characteristics due to the unique charge patterns and shapes of proteins. Here we report protein-intercalated lipid multi-lamellar complexes, denoted ‘proteolipoplexes’, prepared via the electrostatic self-assembly of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) uni-lamellar vesicles (liposomes) with epidermal growth factor (EGF). Anionic EGF with an isoelectric point of 4.6 induces shrinkage and folding of the cationic DOTAP liposomes, and turns it into multi-lamellar lipid complexes. The average diameter of complex is in the range of 150-200 nm as determined by dynamic light scattering (DLS), and the loading efficiency of EGF into the multi-lamellar structures is about 95 %. The formation of multi-lamellar complexes is confirmed by Förster resonance energy transfer (FRET), cryo-transmission electron microscopy (TEM), and small-angle x-ray scattering (SAXS) analysis. Although the proteolipoplex is formed as a multi-lamellar, the average diameter of the complex was not increased significantly, which is different from the mechanism of lipid-DNA lipoplex formation. Langmuir trough analysis reveals that the shrinkage and folding of the DOTAP membrane are induced by the surface pressure asymmetry between outer and inner leaflets in the EGF-interacting lipid bilayer. Moreover, molecular dynamics simulations are performed to understand the multivalent electrostatic interaction and structural change between EGF and DOTAP at atomic level. This study suggests that proteolipoplexes can be easily achieved by the protein-lipid self-assembly and provides insights into structurally controllable nanomaterials.

Electrostatic self-assembly of EGF and DOTAP liposomes into multi-lamellar complexes

254th National Meeting (2017)

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