Raman reporters for SERS/SERRS biosensing and biomedicine: design, applications, and challenges.

Surface-enhanced Raman scattering (SERS) and surface-enhanced resonance Raman scattering (SERRS) offer molecular fingerprint specificity, high sensitivity, narrow spectral bandwidths, and multiplex readout capability for biosensing and biomedical analysis. In reporter-encoded SERS/SERRS nanotags, Raman reporters are key signal-generating molecules that define spectral identity, context-dependent brightness, stability, multiplexing capacity, and quantitative reliability. However, existing reviews have mainly focused on plasmonic substrates, nanotag architectures, assay formats, imaging applications, or spectral-analysis workflows, whereas reporter molecules themselves have been less systematically discussed as molecular and interfacial design variables. This review provides a focused, reporter-centered synthesis of conventional, aromatic thiol/disulfide, Raman-silent-region, near-infrared-resonant/SERRS, responsive, and library-based reporters. We discuss reporter selection principles, reporter-core interactions, immobilization chemistry, surface coverage and orientation, spectral orthogonality, responsive-reporter metrics, multiplex unmixing, machine-learning-assisted spectral decoding, biomolecular scaffolds, and whole-nanoprobe safety. By integrating molecular design, interfacial stability, quantitative performance evaluation, and translational constraints, this review aims to support rational Raman reporter selection, benchmarking, and application-specific deployment.