Nanoplasmonic Sensing of Heterogeneous Extracellular Vesicles: From Bulk to Single Vesicles

Extracellular vesicles (EVs) are heterogeneous nanoscale membrane vesicles released by almost all cell types into the circulation. Depending on their biogenesis and cells of origin, EVs show considerable heterogeneity in their biophysical and biomolecular composition and can serve as reflective and dynamic blood biomarkers for personalized medicine. Conventional analytical technologies, however, often lack the compatibility to reveal nanoscale EV features and resolve vesicle heterogeneity. The past decade has since witnessed the development of various nanoplasmonic technologies to empower EV analysis, through bulk and single-vesicle characterization, at an unprecedented scale and resolution. These platforms achieve versatile measurements that are not only size-matched to EV dimensions but can also probe multiplexed biomolecular contents, thereby providing new insights into EV heterogeneity and enabling transformative clinical opportunities. In this review, key characteristics of EVs and their remarkable heterogeneity are introduced. The sensing principles of plasmonic platforms are also discussed, with recent technology developments highlighted to resolve EV heterogeneity, through bulk analyses of EV subpopulations as well as high-resolution single-EV measurements. An outlook is further provided on emerging opportunities, at the interface of biomarker discovery and technology innovation, to develop empowering nanoplasmonic EV platforms for personalized medicine. biosensing; bulk analysis; extracellular vesicles; nanoplasmonics; single-vesicle analysis.