Enhancing Electrochemical Biosensing of Circulating Nucleic Acids at the Electrode-Biomolecule-Electrolyte Interfaces

The detection and analysis of circulating cell-free nucleic acid (ccfNA) biomolecules are redefining a new era of molecular targeted cancer therapies. However, the clinical translation of electrochemical ccfNA biosensing remains hindered by unresolved challenges in analytical specificity and sensitivity. In this Perspective, we present a novel electrochemical framework for improving ccfNA biosensor performance by optimizing the critical electrode-biomolecules-electrolyte interfaces. We highlight and elucidate related research works on modification-free electrode sensor surfaces, nucleic acids as biological scaffolds, and redesigning redox reporter systems. We conclude by providing an outlook into the future research developments of ccfNA electrochemical biosensing, emphasizing the potential to overcome current analytical limitations by controlling the complex interplay of target biomolecules and redox species at the electrode surface. These advances are poised to significantly impact the development of electrochemical ccfNA technologies, improving both cancer diagnostics and therapeutic monitoring.