HTGAA 2026: Individual Final Project Documentation SECTION 1: ABSTRACT Minimally invasive diagnostics based on the skin’s interstitial fluid (ISF) offer a promising alternative to blood-based testing, with at least 65 biomarkers potentially detectable from ISF. However, achieving sufficient sensitivity and specificity for large proteins remains a challenge due to lower analyte concentrations for high-molecular-weight targets. Aptamer-based or nanobody-based biosensors face limitations individually for this application; hybrid detection modalities combining both elements are emerging to address this gap. This project develops a computational workflow for the rational design of binders targeting ferritin heavy chain (FRIH), an iron storage protein for which no minimally invasive biosensor currently exists. Using RNAfold secondary structure analysis, 100 candidate ssDNA sequences (40 nt) were screened and filtered by minimum free energy criteria. A proximity ligation assay (PLA) framework was proposed to de-risk molecular recognition before device integration, combining a Nb72 nanobody capture probe with a FRIH-directed DNA aptamer reporter in an electrochemical detection architecture. The workflow is broadly adaptable and can be optimized for other clinically important biomarkers, including inflammatory proteins (CRP, IL-6) and cardiac markers (NT-proBNP), supporting a scalable route from computational design to clinical biosensor deployment.