Significance
In the present work nanoliquid chromatography tandem mass spectrometry was used to characterize the protein corona of five different liposome formulations after exposure to mouse and human plasma. The modern proteomic methods employed have clarified that the arrangement of lipid functional groups is a key player that regulates the liposome-protein interactions. We also clarified that the protein corona enrichment and complexity depend on the serum type. Our results suggest that the translational of novel pharmaceutical formulations from animal models to the clinic must be evaluated on a case-by-case basis.