Single-molecule surface-enhanced Raman scattering: From exceptional sensitivity to reliable interpretation

Abstract

Single-molecule surface-enhanced Raman scattering (SM-SERS) should no longer be judged mainly by whether it can detect Raman signals from individual molecules but by what conclusions those signals can support under heterogeneous local conditions. In the single-molecule regime, the recorded spectrum is the product of a coupled molecule–interface–nanocavity–excitation–detection system, shaped by local geometry, molecule–metal coupling, cavity evolution, and readout conditions. The central challenge, therefore, shifts from achieving extreme enhancement to defining measurement conditions well enough for reliable interpretation. Here, we propose different evidential standards for four classes of SM-SERS claims—occupancy, assignment, local state, and mechanism—and argue that multimodal and correlative validation should increase with the strength of the claim. We assess how major platform classes reduce different sources of uncertainty and identify the field’s most tractable priorities: transparent reporting of observables, assumptions, and data-processing pipelines; quantitative statistics and reproducibility metrics for the events on which conclusions rest; and hypothesis-driven controls matched to the claim being made. SM-SERS will become a trustworthy nanospectroscopic tool only when each claim is supported by evidence strong enough to address the uncertainties of the coupled local system that produced the spectrum.