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Research into extracellular vesicles (EVs) has grown significantly over the last few decades with EVs being widely regarded as a source of biomarkers for human health and disease with massive clinical potential. Secreted by every cell type in the body, EVs report on the internal cellular conditions across all tissue types. Their presence in readily accessible biofluids makes the potential of EV biosensing highly attractive as a noninvasive diagnostic platform via liquid biopsies. However, their small size (50-250 nm), inherent heterogeneity, and the complexity of the native biofluids introduce challenges for effective characterization, thus, limiting their clinical utility. This has led to a surge in the development of various novel EV biosensing techniques, with capabilities beyond those of conventional methods that have been directly transferred from cell biology. In this review, key detection principles used for EV biosensing are summarized, with a focus on some of the most recent and fundamental developments in the field over the last 5 years. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > In Vitro Nanoparticle-Based Sensing., (© 2022 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

The biomolecular contents of extracellular vesicles, such as exosomes, have been shown to be crucial in intercellular communication and disease propagation. As a result, there has been a recent surge in the exploration of novel biosensing platforms that can sensitively and specifically detect exosomal content such as proteins and nucleic acids, with a view toward application in diagnostic assays. Here, we demonstrate dual-mode and label-free detection of plasma exosomes using an electrochemical quartz crystal microbalance with dissipation monitoring (EQCM-D). The platform adopts a direct immunosensing approach to effectively capture exosomes via their surface protein expression of CD63. By combining QCM-D with a tandem in situ electrochemical impedance spectroscopy measurement, we are able to demonstrate relationships between mass, viscoelasticity and impedance inducing properties of each functional layer and analyte. In addition to lowering the limit of detection (by a factor of 2-4) to 6.71 × 10 7 exosome-sized particles (ESP) per mL in 25% v/v serum, the synergy between dissipation and impedance response introduces improved sensing specificity by offering further distinction between soft and rigid analytes, thereby promoting EQCM-D as an important technique for exosome analysis.