Nanoparticulated vesicles were widely used for carriers of drugs and imaging probes. To improve the targeting delivery efficiency of these vesicles, ligands were often functionalized onto their surfaces. However, the interaction between vesicles and plasma proteins may cover the ligands and hinder the targeting delivery. It is important to address the potential influence of ligands modification on plasma protein adsorption and the following targeting delivery. In this study, two common used ligands were chosen as the model: transferrin and RGD peptide. Gold nanoparticles were utilized as model particles. Sodium dodecyl sulfate polyacrylamide gel electrophoresis data demonstrated that higher PEG modification and smaller particle size could reduce the plasma protein adsorption, while ligand modification could increase. The cellular uptake results showed that the targeting ability of smaller ligand RGD peptide would be more easily influenced by the proteins corona.