Chemical Biology Drives Membrane-Curvature-Sensing Peptide Probes for Extracellular Vesicle Capture and Applications

Extracellular vesicles (EVs) are nanosized lipid bilayer vesicles released by all cells. EVs carry nucleic acids, proteins, lipids, and metabolites in intercellular communication. As potential liquid-biopsy biomarkers and drug-delivery vehicles for diseases, however, isolating specific EV subpopulations remains challenging owing to their high heterogeneity in size, density, and surface protein markers. We utilized chemical biology tools to develop EV membrane-curvature probes, including MARCKS-ED and other peptides. These short, membrane-anchoring peptides detect the fluid membrane of EVs and report membrane curvature. Here, we review the peptide selection principles, bioorthogonal reaction engineering mechanisms, and applications of these EV peptide probes and discuss future directions, such as stimulus-responsive or artificial intelligence-assisted peptide probe design for on-demand EV capture and subpopulation.