Surface-Enhanced Raman Spectroscopy for Biomedical Applications:Recent Advances and Future Challenges

The year 2024 marks the 50th anniversary of thediscovery of surface-enhanced Raman spectroscopy (SERS). Overrecent years, SERS has experienced rapid development and became acritical tool in biomedicine with its unparalleled sensitivity andmolecular specificity. This review summarizes the advancements andchallenges in SERS substrates, nanotags, instrumentation, andspectral analysis for biomedical applications. We highlight the keydevelopments in colloidal and solid SERS substrates, with anemphasis on surface chemistry, hotspot design, and 3D hydrogelplasmonic architectures. Additionally, we introduce recent innova-tions in SERS nanotags, including those with interior gaps,orthogonal Raman reporters, and near-infrared-II-responsive proper-ties, along with biomimetic coatings. Emerging technologies such asoptical tweezers, plasmonic nanopores, and wearable sensors have expanded SERS capabilities for single-cell and single-moleculeanalysis. Advances in spectral analysis, including signal digitalization, denoising, and deep learning algorithms, have improved thequantification of complex biological data. Finally, this review discusses SERS biomedical applications in nucleic acid detection,protein characterization, metabolite analysis, single-cell monitoring, and in vivo deep Raman spectroscopy, emphasizing its potentialfor liquid biopsy, metabolic phenotyping, and extracellular vesicle diagnostics. The review concludes with a perspective on clinicaltranslation of SERS, addressing commercialization potentials and the challenges in deep tissue in vivo sensing and imaging