Molecular Engineering of an Isomeric Raman Reporter Palette With Synergistic Multidimensional Enhancement for Point‐of‐Care SERS Screening of Respiratory Pathogens

ABSTRACT Surface‐enhanced Raman scattering (SERS) combines molecular‐specific fingerprints and signal amplification, making it ideally suited for multiplexed point‐of‐care (POC) diagnostics. Yet, the translation of SERS into practical use has been hindered by the empirical screening of Raman reporters without rational spectral tunability and the lack of rigorous validation in large clinical cohorts using handheld instrumentation. To this end, we introduce a principle‐driven molecular engineering approach to create a palette of tunable isomeric Raman reporters with clinical validation through large‐scale respiratory pathogen screening. Guided by molecular symmetry principles and electronic effects, we construct an isomeric palette of 24 Raman reporters with unique vibrational signatures. These reporters are enhanced by a multilayer Ag‐on‐Cu reporter structures (MARS) and a sub‐10 nm engineered nanogap SERS enhancer (SENSE) array to maximize signal amplification. The integrated isomeric‐MARS‐SENSE platform enables the simultaneous identification of six respiratory pathogens in 139 clinical nasal swab samples using a handheld Raman spectrometer, achieving satisfactory sensitivity, specificity, and accuracy comparable to RT‐PCR. By combining rational molecular design with robust clinical validation, we expect this work to advance next‐generation multiplexed SERS diagnostics at the POC.