Pancreatic ductal adenocarcinoma (PDAC) has the lowest 5-year survival rate of all major malignancies (11%). In particular, late-stage malignancies have only a 5% 5-year survival rate, whereas early-stage malignancies have a 4 times higher 5-year survival rate. Unfortunately, only 20% of malignancies are caught in early stages. Liquid biopsy has emerged as a possible solution for cancer screening since it allows less invasive, un-biased and serial analysis of cancer biomarkers from the same individual. The most notorious limitation of liquid biopsy is the signal-to-noise ratio (SNR) of cancer-related biomarkers since cancer cells make up a tiny fraction of the total number of cells in the body. To improve patient outcomes through early cancer screening, innovative liquid biopsy PDAC-specific biomarkers with enhanced SNR must be found and validated. The following set of studies combines engineering, biology, biotechnology, and nanotechnology to produce innovative PDAC screening tools with enhanced SNR compared to traditional technologies.