Low molecular weight (LMW) peptides, rather than bulky and abundant proteins, are more viable sources of biomarkers; disease-associated peptides (secreted by cells, shed from their surface or otherwise released) are more likely to enter the bloodstream where we can quickly and easily survey them as part of an early detection strategy for health care. However, despite great investment of resources, efforts to identify serological protein/genetic biomarkers for most diseases have met with limited success. Most current techniques can only capture high molecular weight (HMW) proteins, whereas the real information encoded within low-abundance, small peptides remains elusive, hindering our true understanding of the immunologic process of disease malignance and our ability to detect its early stage with any real accuracy. Our research design addresses current conceptual and technical gaps. We have developed a tunable, nanopore-based platform to effectively fractionate peptides from blood samples with little to no sample processing. With the superior capillary adsorption of nanopore films to peptides via engineering of the nanopore’s physico-chemical properties (e.g., pore size, pore structure, surface affinity), we have been able to enrich these LMW peptides from serum and preserve their integrity. By coupling this platform to advanced mass spectrometry technology and customized biostatistics methods, our discoveries have enormous promise for rapid translation to the clinic, particularly by offering an inexpensive and precise platform for disease diagnosis in vulnerable populations. The examples below highlight our contribution to this field.