Noncontact Mode Surface-Enhanced Raman Spectroscopy Analysis Empowered by Molecular-Scaffold-Gifting Au Nanochannel.

Label-free quantitative detection of chemically diverse molecules is of critical importance across fields spanning medical diagnostics, food safety, and law enforcement. Surface-enhanced Raman spectroscopy (SERS) provides powerful molecular identification through fingerprint spectra, capable of achieving single-molecule detection limits when analytes are positioned directly at the plasmonic hotspots of Au/Ag substrates. Yet conventional contact-mode SERS, which relies on the direct adsorption of analytes onto bare metal surfaces, is limited by poor reproducibility and signal heterogeneity arising from random molecular orientations and competitive binding. Here, we present a proof-of-concept noncontact mode SERS platform that routinely delivers reproducible, predictable, and quantitative spectra readout, including discrimination of subtle enantiomeric differences. This platform utilizes fluorenylmethoxycarbonyl-lysine (Fmoc-Lys) scaffolds confined within 1-2 nm channels of nanoporous gold nanospheres. The Fmoc core captures target analytes through hydrophobic interactions, while the chiral center regulates the adsorption configuration/strength. This design fixes analyte distance and orientation relative to the metal surface, thereby minimizing stochastic spectral variation. We applied this platform to quantitatively analyzed methamphetamine (METH), a globally prevalent abused drug, in complex human urine samples and achieved accuracy comparable to mass spectrometry without requiring analyte-specific reference spectra. Our results highlight noncontact SERS as a general strategy for reliable, ultrasensitive molecular analysis, especially for targets lacking standard spectral libraries.