Dissecting the Extracellular Vesicle Protein Corona: Proteomic Challenges and Opportunities for Understanding EV Biology and Function

Extracellular Vesicles (EVs) are lipid bilayer nanoparticles released by all cell types. They are increasingly studied as sources of molecular information for diagnostics, biomarker discovery, and therapeutic applications. When EVs come into contact with biofluids, they rapidly acquire a layer of adsorbed molecules, known as the biomolecular corona, which consists mainly of proteins. This protein corona can mask or remodel the native EV surface, influence biological interactions, and alter the protein profiles detected by mass spectrometry-based proteomics. As a result, some molecular signatures attributed to EVs may derive from the corona rather than from the vesicles themselves. This is an important source of variability in EV proteomic studies and can affect biomarker interpretation and therapeutic development. Conversely, the protein corona may itself contain biologically relevant information, because it reflects how EVs interact with their physiological or pathological environment. This review summarizes recent advances in EV protein corona research, the main proteomic approaches used for its characterization, and its relevance to EV biology, diagnostics, biomarker discovery, and therapeutic applications.