Single-Molecule Surface-Enhanced Raman Spectroscopy

Single-molecule surface-enhanced Raman spectroscopy (SM-SERS) exploits the intense electromagnetic fields generated by plasmonic nanostructures to amplify the inherently weak Raman scattering of individual molecules. By engineering nanoscale gaps or “hotspots” between metallic features, Raman signals can be enhanced by as much as 10¹⁰–10¹⁶, enabling non-invasive, label-free detection of single entities. This level of sensitivity opens a window onto molecular heterogeneity and dynamics, offering insight into reaction mechanisms, conformational changes and intermolecular interactions in real time. Key strategies include optimisation of nanoparticle geometry, use of two-dimensional materials for chemical enhancement, dynamic trapping of molecules within tailored cavities and the integration of resonance effects. Despite substantial progress, challenges remain in controlling hotspot reproducibility, minimising photodegradation and reliably correlating signal fluctuations with molecular behaviour. Advances in substrate design, statistical validation methods and the integration of complementary spectroscopic or microscopic modalities continue to expand the scope of SM-SERS across chemistry, materials science and biomedical diagnostics.

Research from Nature Portfolio

Recent studies have introduced patterned plasmonic trimers that combine dimers with a central trap particle to direct probe molecules into precisely defined hotspots. This configuration achieves single-molecule sensitivity down to 10⁻¹⁴ M for various thiolated reporters and demonstrates bi-analyte approaches to confirm true single-molecule events. The method has been applied to the early detection and subtyping of lung tumours, distinguishing adenocarcinoma from other tissue types on fresh biopsy samples. In parallel, optical plasmonic tweezers have been devised to form dynamic nanocavities under laser illumination, reducing the detection volume in aqueous media and providing reproducible field enhancements. This platform has enabled high-throughput characterisation of individual peptide species during amyloidogenesis, revealing low-population transient conformers under physiological pH conditions and offering mechanistic insight into fibril initiation.

Research from all publishers

A synergistic enhancement strategy has been demonstrated by integrating monolayer WS₂ and ultrathin oxide layers with gold nanogaps to achieve combined electromagnetic and chemical amplification. This hybrid architecture affords enhancement factors exceeding 10¹⁶ and allows unambiguous observation of single-molecule Raman spectra at concentrations as low as 10⁻¹⁸ M. A comprehensive review of SM-SERS implementations highlights advances in ultra-high-EF substrates, reproducibility-focused fabrication, hotspot-localisation strategies and the emergence of non-metallic or hybrid platforms. The survey contextualises applications ranging from catalytic reaction monitoring to nanoelectronic device characterisation. Moreover, a gold nanoparticle-based sensor has been employed for real-time, label-free monitoring of tyrosine phosphorylation, enabling dynamic tracking of kinase activity via discrete SERS spectral changes and offering a new route to assess enzyme kinetics at the single-molecule level.

Single-Molecule Surface-Enhanced Raman Spectroscopy publication trend

The graph below shows the total number of articles in single-molecule surface-enhanced raman spectroscopy across all publications each year (not limited to Nature Index journals).

Technical terms

Surface plasmon resonance: Collective oscillation of conduction electrons at a metal–dielectric interface, excited by incident light.

Hotspot: Nanoscale region where the local electromagnetic field is greatly intensified, driving large Raman signal enhancement.

Enhancement factor: Ratio quantifying the amplification of Raman intensity by a plasmonic substrate relative to a non-enhancing reference.

Electromagnetic enhancement: Amplification of Raman scattering due to increased local field intensity from plasmonic resonance.

Chemical enhancement: Contribution to Raman signal intensity arising from charge-transfer interactions between adsorbed molecules and the substrate.

Bi-analyte method: Statistical approach using two distinct probe molecules to validate that observed signals originate from individual species.

References

1. Observation of single-molecule Raman spectroscopy enabled by synergic electromagnetic and chemical enhancement. PhotoniX (2024).
2. Plasmonic trimers designed as SERS-active chemical traps for subtyping of lung tumors. Nature Communications (2024).
3. Label-Free SERS Sensors for Real-Time Monitoring of Tyrosine Phosphorylation. Analytical Chemistry (2024).
4. Efficient optical plasmonic tweezer-controlled single-molecule SERS characterization of pH-dependent amylin species in aqueous milieus. Nature Communications (2023).
5. Single-Molecule Surface-Enhanced Raman Spectroscopy. Sensors (2022).