What Does SERS Measure in Nucleic Acids? An Interface-Defined Perspective

Surface-enhanced Raman scattering (SERS) has emerged as a powerful platform for nucleic acids analyses due to its ultrahigh sensitivity and intrinsic molecular specificity. However, unlike small-molecule systems, SERS responses of nucleic acids remain highly variable and strongly dependent on experimental conditions, limiting structural interpretability and reproducibility. In this Review, we provide a unified perspective that reframes SERS of nucleic acids as an interface-defined physicochemical process rather than a direct molecular fingerprinting technique. We systematically analyze how interfacial accessibility, adsorption configuration, conformational reorganization, and electromagnetic (EM) selection collectively govern spectral formation through a hierarchical selection mechanism. On this basis, we propose that SERS spectra predominantly encode ensembles of interface-selected conformations, which generally diverge from intrinsic solution-phase structures, thereby explaining the widespread inconsistencies observed across different studies. This framework establishes a conceptual foundation for transforming SERS of nucleic acids from an empirical sensing approach into a controllable and predictive platform for structural analysis and biosensing applications.