When nanoparticles (NPs) are exposed to biological fluids they adsorb biomolecules (mainly proteins) to form a protein corona. We have applied nanoliquid-cromatography mass spectroscopy (NanoLC-MS/MS) to quantitatively determine the proteins associated with several lipid NP formulations after incubation with human plasma (HP). By NanoLC-MS/MS we identified vitronectin as the most promising protein corona component for active targeting. To exploit the "protein corona effect" we investigated the interactions of l, 2-dioleoyl-3-trimethylammonium propane (DOTAP)/DNA cationic liposome/DNA complexes (lipoplexes) with target cells. By applying two-color fluorescence laser scanning confocal microscopy (LSCM) we demonstrate that vitronectin directs a receptor-mediated uptake of lipoplexes into target cells. This experiment sets the basis for a rational exploitation of the protein corona for targeted drug and gene delivery.