Surface-Enhanced Raman Spectroscopy in Protein Detection

Surface-Enhanced Raman Spectroscopy (SERS) harnesses the plasmonic properties of metal nanostructures to amplify the intrinsic vibrational signatures of proteins, enabling detection at physiological and even single-molecule concentrations. By positioning proteins in close proximity to engineered surfaces—most often silver or gold nanoparticles, nanostructured films or dynamic hotspots—the local electromagnetic field is dramatically enhanced, leading to Raman scattering intensities several orders of magnitude greater than conventional Raman spectroscopy. This approach allows label-free analysis of protein conformation, dynamics and interactions under near-native conditions. Recent advances in instrumentation and substrate design have addressed longstanding challenges in reproducibility, sensitivity and specificity, facilitating applications ranging from real-time monitoring of folding pathways and aggregation states to direct discrimination of disease biomarkers in complex biofluids. Integration with microfluidic platforms, optical manipulation tools and statistical methods has further expanded the scope of SERS for detailed characterisation of transient species, membrane-protein interactions and quantitative imaging of protein distributions in biological samples.

Research from Nature Portfolio

Recent studies have demonstrated the combination of optical tweezers with nanoparticle-coated beads to create a tunable SERS hotspot that traps single proteins within a microfluidic flow chamber. This configuration yields highly reproducible enhancements and resolves structural heterogeneity of globular proteins and transient oligomeric species at physiological concentrations. In a complementary approach, controlled evaporation in an optofluidic microwell has been used to assemble protein domains at a liquid edge, preserving native conformations while concentrating analytes at mesoscale assemblies. The addition of a plasmonic coating to the microwell wall further amplifies the Raman signal, achieving sub-micromolar detection limits without denaturation and demonstrating the feasibility of high-quality, high-sensitivity spectral collection under dynamic conditions.

Surface-Enhanced Raman Spectroscopy in Protein Detection publication trend

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

Technical terms

Surface-Enhanced Raman Spectroscopy (SERS): enhancement of Raman scattering by molecules at or near a plasmonic surface, enabling sensitive vibrational fingerprinting of biomolecules.

Plasmonic hotspot: a highly localised region of amplified electromagnetic field on a metallic nanostructure where Raman signals are greatly intensified.

Optical tweezers: a laser-based technique for non-contact trapping and manipulation of microscopic particles, used here to position and control nanostructured SERS substrates.

Correlation coefficient analysis: a statistical method for quantifying the similarity between SERS spectra, often used to assess the native state of proteins.

References

1. Optical tweezers-controlled hotspot for sensitive and reproducible surface-enhanced Raman spectroscopy characterization of native protein structures. Nature Communications (2021).
2. Triggering molecular assembly at the mesoscale for advanced Raman detection of proteins in liquid. Scientific Reports (2018).
3. Protein Quantification and Imaging by Surface‐Enhanced Raman Spectroscopy and Similarity Analysis. Advanced Science (2020).
4. Correlation coefficient-directed label-free characterization of native proteins by surface-enhanced Raman spectroscopy. Chemical Science (2022).
5. Tunable lipid-coated nanoporous silver sheet for characterization of protein-membrane interactions by surface-enhanced Raman scattering (SERS). Analytical and Bioanalytical Chemistry (2023).