AI/ML-Assisted SERS Biosensing for Biomolecular Detection: From Direct Spectral Response to Integrated Diagnostic Systems

Surface-enhanced Raman scattering (SERS) offers a powerful route for biomolecular detection because it combines molecular specificity with high sensitivity, rapid optical readout, and multiplexing capability. In real biological samples, however, analytical performance is rarely determined by signal enhancement alone. Biofluids such as serum, plasma, saliva, urine, and interstitial fluid contain complex biomolecular mixtures that interfere with target capture, spectral response, and data interpretation. A practical SERS biosensor must therefore localize targets, stabilize spectral responses, tolerate matrix-induced variation, and convert complex spectra into reliable analytical information. This review discusses recent progress in SERS biosensing from an integrated system perspective, with particular focus on artificial intelligence/machine learning (AI/ML)-assisted interpretation. Direct label-free SERS provides chemically transparent readouts but is limited by stochastic adsorption, hotspot heterogeneity, and spectral variation in complex samples. Bio-recognition interfaces improve target localization, while signal-transduction strategies based on nanotags, immunoassays, clustered regularly interspaced short palindromic repeats (CRISPR) systems, nanozymes, and lateral-flow formats decouple molecular recognition from spectral generation. Digital SERS further improves measurement robustness by converting fluctuating intensities into countable, event-based outputs. AI/ML-assisted analysis can support full-spectrum classification, calibration transfer, explainability, and patient-level decision-making. We frame AI/ML-assisted SERS biosensing as an integrated architecture connecting substrate design, interface engineering, signal transduction, digital measurement, and clinical validation. Future progress will depend as much on validation-ready workflows as on plasmonic enhancement itself, especially for systems intended to operate across different samples, instruments, and clinical settings.