(311a) Challenge and Promise of Extracellular Nanovesicles in Early Detection and Treatment of Cancer and Other Systemic Diseases

Exosomes and other nano-size extracellular vesicles (EVs) are stable membrane-bound nanoparticles secreted into the circulation by diverse cell types, including epithelial cells, mesenchymal cells, lymphocytes, and tumor cells. They are 20-120 nm in diameter and contain membrane and cargo, which includes nucleic acids and proteins, originating from the parent cell. They are found in astronomical numbers in extracellular spaces and body fluids, including blood, urine, saliva, breast milk, semen, lymphatic, and spinal fluids. In blood alone, there are over 10¹⁶ circulating exosomes, the physiological functions of which are not completely understood. It has already been shown that exosomes are important in modulating immune response and are thought to play a role in short and long-range intercellular signaling by fusing with recipient cells and releasing their cargo. Their population is heterogeneous, reflecting the diversity of cells that secrete them which, in patients, include abnormal (e.g. malignant) cells. The stability of these vesicles allows their isolation from body fluids, characterization by molecular content and biophysical properties, which together can potentially be used for medical diagnostics. However, the fundamental difficulty in using molecular content of exosomes in early and routine diagnostics is the large background of nanovesicles originating from normal cells found in the circulation that interferes with the analysis even when the most sensitive techniques (such as digital droplet PCR) are used. Our laboratory has focused on identifying biophysical properties of cancer exosomes that most distinguish them from other nanovesicles in the blood and use these properties to fractionate the sample and enrich in tumor exosomes. In this approach, we aim to decrease the influence of the background in order to improve the accuracy of downstream molecular measurements, ultimately improving the sensitivity to allow for an early detection of cancer and other systemic diseases.