Unraveling the Role of Tumor Extracellular Vesicles in Angiogenesis to Inform the Design of Biomimetic Electronic Devices

Abstract

Extracellular vesicles (EVs) are lipid-bilayer particles secreted by various types of cells, including tumor cells. EVs are enriched with a discrete set of bioactive cargoes they can transfer to cells in both adjacent and distant sites to orchestrate multiple key pathophysiological events such as angiogenesis and cancer progression. Although several studies have emerged to probe and characterize these particles, the mechanisms involved in how EVs mediate their cargo transfers are still poorly understood. Accordingly, the development of model systems that may be able to recapitulate and expound upon these mechanisms have become attractive targets. Individually, supported lipid bilayers (SLBs) and organic electrochemical transistors (OECTs) have emerged as novel methods to study and monitor cellular functions. When combined, they have the potential to represent a versatile electronic biosensor capable of monitoring the properties and behavior of mammalian cell surfaces. Here, this hybrid SLB-OECT system is intended to analyze tumor EV (TEV) processes like binding, fusion, and potentially cargo transfer processes on model cell membranes in real-time. In this work, the interactions between TEVs and epithelial cells were studied to assess their ability to induce angiogenesis. The analyses revealed enhanced proangiogenic activity via Vascular Endothelial Growth Factor (VEGF) upregulation amongst cells infected with TEVs. In an effort to evade the effects of TEV exposure, they were treated with heparin to prevent the binding and uptake of TEVs by recipient epithelial cells. Cells exposed to heparin-coated TEVs showed minimal VEGF upregulation similar to the VEGF expression observed of untreated cells indicating successful TEV blocking. These results represent important feedback anticipated to aid in optimizing the design of the aforementioned model SLB-OECT device for the in-depth, mechanistic analysis of TEV-mediated processes.