In this study we exposed 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/DNA lipoplexes to different concentrations of human plasma (HP). Liquid chromatography-tandem mass spectrometry showed that the adsorbed protein corona is rich in vitronectin, a major ligand for α vβ 3 or α vβ 5 integrins. To investigate whether the protein corona could dictate a selective access to cells expressing vitronectin receptors, highly-metastatic MDA-MB-435S cells that express high levels of α vβ 3 and α vβ 5 integrins, were used as experimental model. Non-metastatic MCF7 cells that do not express α vβ 3 and express reduced levels of α vβ 5 integrins were used as a reference. After exposure to HP, the cellular uptake of lipoplexes in MDA-MB-435S cells was more than 2-fold larger than that of bare ones, while complexes could not enter MCF7 cells remaining largely accumulated at the plasma membrane. Collectively our data suggest that the protein corona can be used as a novel tool for cancer cell targeting.