Nanostructured materials: shaping the future of electrochemical sensors for DNA methylation detection.

DNA methylation is a key epigenetic modification regulating gene expression without altering the DNA sequence, and its aberrant patterns serve as important biomarkers for cancer and cardiovascular diseases. Electrochemical biosensors have emerged as powerful platforms for site-specific methylation analysis due to their high sensitivity, simplicity, low cost, and compatibility with miniaturized devices. More importantly, electrochemical interfaces enable direct coupling between molecular recognition and nanoscale signal amplification, allowing detection limits to be pushed beyond intrinsic electrochemical constraints. This review presents a mechanism-oriented framework for electrochemical DNA methylation sensing, integrating advances in interfacial signal transduction and nanomaterial-enabled amplification. Emphasis is placed on classifying representative material platforms, including carbon-based nanomaterials, metallic nanostructures, metal-organic frameworks (MOFs)/covalent organic frameworks (COFs) and DNA nanostructures, elucidating their roles in regulating electrochemical responses. In particular, we highlight how these materials modulate interfacial electron-transfer kinetics, adsorption, conductivity, and catalytic activity, governing the translation of methylation events into amplified signals. Finally, we outline emerging directions toward more quantitative and systematic design principles for interfacial biosensing architectures.