Emerging SERS and TERS MoS₂ platforms for the characterization of plasma-derived extracellular vesicles

Extracellular vesicles (EVs) play a crucial role in intercellular communication processes. In addition, their biomolecular cargoes such as lipids, proteins, and nucleic acids are useful for identifying potential biomarkers related to different stages of cancer disease. However, the small size and heterogenicity of tumor-related EVs represent a major challenge in properly identifying the content of EVs' cargoes with common characterization protocols. To address these issues, surface-enhanced Raman spectroscopy (SERS) and tip-enhanced Raman spectroscopy (TERS) are powerful alternatives to assign the vibrational fingerprints to the biomolecules contained in cancer EVs, providing high specificity and spatial resolution. Transition metal dichalcogenides are particularly interesting as SERS and TERS substrates due to the high sensitivity of their 2D surface through coulombic and van der Waals interactions when in contact with an analyte or small object such as the charged membranes of EVs. These interactions induce subtle changes in the work function of the flakes which can be measured through drastic changes of optical processes. We investigate the use of MoS₂ flakes synthesized by atmospheric pressure chemical vapor deposition as a potential label-free SERS and TERS platform for the identification of plasma EVs. To exemplify this technology, we isolated plasma EV samples from donors with early-stage [FIGO (I/II)] with high-grade serous carcinoma (HGSC) by size exclusion chromatography (SEC). Both surface- and tip-enhanced measurements were conducted individually, enabling the identification of a series of markers from ovarian cancer donors, highlighting the complementarity of SERS and TERS measurements.