What the Cell "Sees" in Extracellular Vesicle Biology

About a decade ago, a concept termed "protein corona" revolutionized the nanoscience field giving a whole new level of understanding in how nanoparticles interface with biological systems. The cell "sees" the surrounding proteins, not the bare surface of the nanoparticle. Now, the question is whether this holds true for extracellular vesicles (EVs) – or biological nanoparticles – and how proteins interacting with the EV surface can be studied in isolation from the EV's protein cargo. Here I propose a combination of emerging technologies: 1) enzyme-catalysed proximity labelling for protein-protein interactions, 2) protein tagging to the extracellular loop of a transmembrane protein on EVs, and 3) zebrafish embryos as a model to study tissue- and cell-type-specific EVs in vivo. The marriage of the three is a unique idea seeking to redefine EV biology with a new dimension, fundamentally from the cell's viewpoint.