Next-Generation SERS Probes: Engineering Hotspots, Intelligent Molecular Targeting, and AI-Driven Spectral Analysis...

Surface-enhanced Raman spectroscopy (SERS) has evolved from a fundamental optical phenomenon to a powerful, molecule-specific analytical technique capable of detecting ultra-trace-level species across biomedicine, catalysis, environmental monitoring, and national security applications. In this review, we summarize recent advances in SERS probe design and fabrication along three major directions: (i) engineering plasmonic hotspots with enhanced field confinement to achieve stronger and more uniform signals; (ii) analyte-directed strategies that precisely position and retain target molecules via tailored surface chemistries, nanoscale confinement, and on-surface reactions for single hotspot SERS; and (iii) hybrid architectures integrating plasmonic metals with functional materials, including high entropy materials, semiconductors, and graphene and other 2D materials, to synergistically couple electromagnetic and chemical enhancement mechanisms. Despite significant progress, key challenges remain for practical applications outside laboratories, including substrate reproducibility and stability, diverse analyte compatibility, unknown molecule identification and standardized quantitative performance in complex environments. We highlight emerging solutions, such as large-area nanomanufacturing for controlled nanoscale gaps, high-resolution Raman mapping for spatial-temporal characterization, density-functional-theory-guided molecular interpretation, and machine-learning-enabled spectral analysis. Advances in foundational AI models and data-driven discovery are positioning SERS to become an increasingly versatile platform, from decoding unknown molecular structures to analyzing complicated multi-component systems for environmental, biomedical, and national security applications with high sensitivity and selectivity.