SERS nanotag coatings and surface layers: Critical yet underemphasized contributions to probe stability, sensitivity,...

Surface-enhanced Raman scattering (SERS) nanotags have emerged as powerful bioanalytical probes for cellular and biomolecular detection, offering distinct advantages over conventional fluorescence-based methods, including narrow spectral fingerprints that enable high multiplexing, exceptional photostability, and strong signals in the near-infrared region, where biological interference is minimal. While substantial research has focused on optimizing metallic nanoparticle cores and Raman reporter molecules to enhance signal brightness and achieve attomolar detection limits, the critical role of coatings and surface layers in determining SERS nanotag performance has received comparatively little attention. This review emphasizes how the structure and composition of protective coatings and surface layers significantly influence three key aspects of SERS nanotag functionality: stability, targeting specificity, and signal brightness. We first provide an overview of SERS nanotag architecture. We then examine in detail how coating properties influence colloidal and signal stability, how surface-layer architecture affects cellular targeting specificity and selectivity, and how coatings can modulate signal brightness through a combination of chemical and electromagnetic enhancement mechanisms. We conclude by discussing challenges and opportunities in designing SERS nanotags with engineered coating architectures to maximize both sensitivity and specificity for advanced bioanalytical applications.