Integrated Heterostructure Platform for SERS Fingerprinting of Biomolecules and Mechanistic Deciphering of Photocatalytic Intermediates

Conspectus Surface-enhanced Raman spectroscopy (SERS), which integrates conventional Raman spectroscopy with nanostructured substrates, has emerged as a powerful, nondestructive analytical technique for label-free chemical and biological fingerprinting. Its high sensitivity and noninvasive nature have enabled real-time detection and characterization of DNA, RNA, pathogens, and disease biomarkers. Beyond biomolecular analysis, SERS has demonstrated exceptional capability for identifying, monitoring, and understanding short-lived reaction intermediates, providing critical insights into photocatalytic reaction mechanisms. Consequently, SERS continues to drive advances across chemistry, materials science, biology, and environmental monitoring, with substrate performance being fundamentally determined by the properties of the constituent nanomaterials. Zero-dimensional (0D) plasmonic nanoparticles, one-dimensional (1D) nanowires, nanotubes, and nanorods, as well as two-dimensional (2D) nanosheets, play pivotal roles in Raman signal enhancement through both electromagnetic mechanism (EM) and chemical mechanism (CM) contributions. Despite these advancements, achieving precise nanoscale control over plasmonic nanostructure organization remains a major challenge for reliable molecular fingerprinting. To address this issue, we engineered heterostructure SERS substrates with optimized EM and CM enhancement mechanisms, an emerging strategy at the forefront of SERS substrate design. Leveraging the inherent molecular specificity of Raman spectroscopy, these heterostructures successfully generate characteristic spectral fingerprints of biomolecules, thereby enhancing the sensitivity, selectivity, and reliability of biomolecular detection. In this Account, we present our research efforts toward the design and development of heterostructure-based SERS platforms for label-free molecular recognition, leveraging molecule-specific vibrational fingerprints for sensitive and selective detection. We first introduce our framework for SERS substrate engineering, which integrates precise plasmonic hot spot design to maximize EM enhancement with strategically selected semiconductors, 1D, and 2D materials that promote CM enhancement through efficient interfacial charge transfer. This synergistic design strategy has enabled the development of next-generation SERS substrates that combine ultrahigh sensitivity, excellent signal reproducibility, and application-specific functionality. Drawing on over a decade of research from our laboratory, we next present representative examples of heterostructure-based SERS platforms for biomolecular fingerprinting of viruses, bacteria, and disease-associated biomarkers. We further highlight the broader utility of these SERS platforms in photocatalytic studies, where operando SERS enables real-time monitoring of reactant consumption and product formation while simultaneously capturing the vibrational fingerprints of trace and transient interfacial reaction intermediates. Finally, we discuss the key challenges facing the field and provide perspectives on emerging opportunities and future research directions. We hope that the insights provided herein will serve as a valuable foundation for researchers seeking to develop next-generation, highly reliable heterostructure-based SERS substrates with multifunctional molecular fingerprinting capabilities.