Unveiling the Electrical Properties of Hyaluronan-Coated Cancer Extracellular Vesicles Using Correlative Scanning Probe Microscopy-Based Nano-Electrical Modes

Cancer cells produce extracellular vesicles (EVs) coated with an anionic sugar polymer, hyaluronan (HA), in the extracellular matrix. Hyaluronan is an established cancer biomarker in several cancer types. In this work, we thoroughly investigated the electrical properties of HA-coated EVs using advanced scanning probe microscopy (SPM) based nanoelectrical modes, which include EFM (electrostatic force microscopy), KPFM (Kelvin probe force microscopy), PFM (piezoresponse force microscopy) and C-AFM (conductive atomic force microscopy). Analyses revealed distinct properties for different sets of EVs regarding surface potential, charge distribution, and piezoelectric electro-mechanical response at the single-vesicle resolution. The typical electron transport capabilities are primarily driven by ions in sandwiched EV junctions. This correlative approach essentially could distinguish HA-coated cancer EVs (CEVs) from normal EV (NEVs) counterparts. The combined SPM-based nanoelectrical modes offered a multiplexed one-stop label-free solution for EV's electrical property assessments. This strategy is useful in developing EV-based bioelectronic sensors.