Nanomaterials and nanostructures have unique physico-chemical properties that can be explored to develop nanodiagnostics for multiplex profiling of biomarkers in a blood sample. This presentation will feature three nanodiagnostics to characterise circulating biomarkers in melanoma patients. Firstly, a multiplexed nanoparticle-based barcoding strategy to track phenotypic changes in extracellular vesicles (EVs) is presented. We follow the EVs phenotypic evolution of melanoma patients receiving targeted therapy and find specific EVs profiles involved in the development of drug resistance, reflecting the potential of EVs phenotyping for monitoring treatment responses. To drive EVs-based nanodiagnostic for potential application in melanoma screening, we show how the tuning of nanoscopic fluid flows on the sensor surface of the nanodiagnostic improves detection sensitivity by multiple orders of magnitude and facilitates profiling of four protein biomarkers in serum EVs in early-stage melanoma patients (including in situ melanoma). Lastly, we introduce a digital single molecule sensitive nanodiagnostic that provides a new window into better understanding immune overreactions. This nanodiagnostic combines a nanostructured array with gold-topped nanopillars and plasmonic barcodes for enhanced signal readouts, enabling attomolar detection of four selected cytokines in plasma. Through longitudinal tracking of these cytokines in melanoma patients receiving immunotherapy, we identify a trace cytokine signature that could serve as an indicator for the onset of immune toxicities with potential for early therapeutic adjustment.