Toward Quantitative Surface-Enhanced Raman Scattering with Plasmonic Nanoparticles: Multiscale View on Heterogeneities in Particle Morphology, Surface Modification, Interface, and Analytical Protocols.

Surface-enhanced Raman scattering (SERS) provides significantly enhanced Raman scattering signals from molecules adsorbed on plasmonic nanostructures, as well as the molecules' vibrational fingerprints. Plasmonic nanoparticle systems are particularly powerful for SERS substrates as they provide a wide range of structural features and plasmonic couplings to boost the enhancement, often up to >10 ⁸ -10 ¹⁰ . Nevertheless, nanoparticle-based SERS is not widely utilized as a means for reliable quantitative measurement of molecules largely due to limited controllability, uniformity, and scalability of plasmonic nanoparticles, poor molecular modification chemistry, and a lack of widely used analytical protocols for SERS. Furthermore, multiscale issues with plasmonic nanoparticle systems that range from atomic and molecular scales to assembled nanostructure scale are difficult to simultaneously control, analyze, and address. In this perspective, we introduce and discuss the design principles and key issues in preparing SERS nanoparticle substrates and the recent studies on the uniform and controllable synthesis and newly emerging machine learning-based analysis of plasmonic nanoparticle systems for quantitative SERS. Specifically, the multiscale point of view with plasmonic nanoparticle systems toward quantitative SERS is provided throughout this perspective. Furthermore, issues with correctly estimating and comparing SERS enhancement factors are discussed, and newly emerging statistical and artificial intelligence approaches for analyzing complex SERS systems are introduced and scrutinized to address challenges that cannot be fully resolved through synthetic improvements.