Surface-Enhanced Raman Scattering-Based Multimodal Techniques: Advances and Perspectives

Surface-enhanced Raman scattering (SERS) spectroscopy is a versatile molecular fingerprinting technique with rapid signal readout, high aqueous compatibility, and portability. To translate SERS for real-world applications, it is pertinent to overcome inherent challenges, including high sample variability and heterogeneity, matrix effects, and nonlinear SERS signal responses of different analytes in complex (bio)chemical matrices with numerous interfering species. In this perspective, we highlight emerging SERS-based multimodal techniques to address the key roadblocks to improving the sensitivity, specificity, and reliability of (bio)chemical detection, bioimaging, theragnosis, and theragnostic. SERS-based multimodal techniques can be broadly categorized into two categories: (1) complementary methods or systems that work together to achieve a common goal where each method compensates for the weaknesses of the other to culminate in a single enhanced outcome or (2) orthogonal techniques that are independent and provide separate but corroborating results simultaneously without interfering with each other. These multimodal techniques maximize information gained from a single experiment to achieve enhanced qualitative or quantitative analysis and broaden the range of detectable analytes from small molecules to tissues. Finally, we discuss emerging directions in multimodal platform design, instrument integration, and data analytics that aim to push the analytical limits of holistic detection.