<i>Quo Vadis</i> , Electrochemical DNA Biosensor? Lessons from Three Decades of SNP Sensing

Electrochemical DNA biosensors have been studied for over three decades, producing thousands of publications and a sophisticated engineering toolkit. However, a broad clinical adoption remains limited. The COVID-19 pandemic served as a stress test-global demand, unprecedented funding, accelerated regulatory pathways, and a clearly defined genomic target-yet electrochemical nucleic acid biosensors played no meaningful role in the diagnostic response, indicating that the barriers to translation are structural. Here, rather than cataloguing sensing formats, we analyze the field framing progress through three interacting constraints focusing on single-nucleotide polymorphism (SNP) sensing: the biological realities of nucleic acid targets, the physical limits of surface-based hybridization, and the clinical/market environment that governs adoption. We find that many advances optimize analytical performance under laboratory conditions while leaving application complexity largely unresolved. Yet, viable niches emerge at the intersection of low information complexity and operational urgency-rapid pharmacogenomic genotyping, now driven by directive clinical guidelines, and infection diagnostics, where simplicity matters more than sophistication. A broader redirection emerges when DNA acts not as the analyte but as a functional tool: Electrochemical aptamer-based sensors are entering commercial markets; nuclease and enzymatic activity profiling exploits the regime where these sensors perform best; and therapeutic oligonucleotides-invisible to standard sequencing workflows-map naturally onto the platform's strengths. The field's most transferable contribution may not be DNA detection itself, but the programmable molecular interfaces it has developed.