Surface-Enhanced Raman Spectroscopy in Live Cell Imaging

Surface-Enhanced Raman Spectroscopy (SERS) has emerged as a transformative tool for non-invasive, chemically specific imaging of living cells. By exploiting the plasmonic amplification of Raman scattering signals at metallic nanostructures, SERS enables the detection of molecular vibrations with ultrahigh sensitivity and spatial resolution down to the single-cell and subcellular level. Recent advances in nanoparticle design, including graphene-isolated gold cores, polydiacetylene coatings and alkyne-functionalised clusters, have addressed key challenges such as biocompatibility, photostability and background interference. These developments allow real-time monitoring of biomolecules—including metabolites, redox species and neurotransmitters—within the complex intracellular milieu. The ability to operate in the so-called Raman-silent window minimises spectral overlap with endogenous cellular components, facilitating multiplexed mapping of organelles and dynamic processes. Collectively, these innovations have broadened the scope of SERS from static label-based assays to live-cell functional imaging, offering new insights into cell signalling, drug delivery and disease pathology.

Research from Nature Portfolio

Recent studies have introduced ultrastrong bioorthogonal probes based on polydiacetylenes that possess intrinsic alkyne vibrational modes in the cellular Raman-silent region. These water-soluble polymers achieve enhancement factors up to 10^4 compared with conventional tags, enabling high-contrast stimulated Raman scattering imaging of organelles without additional enhancers. In parallel, the assembly of alkyne-silver nanoparticle clusters has been demonstrated for live intracellular mapping of dopamine. By linking colloidal silver particles with alkyne-dopamine conjugates, researchers have achieved tight interparticle gaps that generate strong local fields, allowing direct visualisation of neurotransmitter distribution across the cytoplasm in real time.

Surface-Enhanced Raman Spectroscopy in Live Cell Imaging publication trend

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

Technical terms

Surface-Enhanced Raman Spectroscopy (SERS): A technique that amplifies Raman scattering signals by several orders of magnitude using plasmonic nanostructures.

Raman-silent region: A spectral window (ca. 1,800–2,800 cm^–1) where endogenous cellular signals are minimal, enabling clear detection of labelled vibrational modes.

Plasmonic nanoparticle: A metallic particle, typically gold or silver, that supports surface plasmons and enhances local electromagnetic fields.

Bioorthogonal probe: A molecular label that undergoes selective chemical reactions in living systems without interfering with native biochemistry.

Nanoreactor: A confined nanoscale environment combining catalytic and plasmonic components to facilitate both biochemical reactions and SERS readout.

Stimulated Raman scattering (SRS): A coherent Raman technique that increases imaging speed and sensitivity by stimulating specific vibrational transitions.

References

1. Fabrication of Graphene-isolated-Au-nanocrystal Nanostructures for Multimodal Cell Imaging and Photothermal-enhanced Chemotherapy. Scientific Reports (2014).
2. Polydiacetylene-based ultrastrong bioorthogonal Raman probes for targeted live-cell Raman imaging. Nature Communications (2020).
3. Isotopic graphene–isolated-Au-nanocrystals with cellular Raman-silent signals for cancer cell pattern recognition. Chemical Science (2018).
4. Live Intracellular Biorthogonal Imaging by Surface Enhanced Raman Spectroscopy using Alkyne-Silver Nanoparticles Clusters. Scientific Reports (2018).
5. Dynamic monitoring and quantitative characterization of intracellular H2O2 content by using SERS based boric acid nanoprobe. Talanta (2020).
6. A Bimodal Fluorescence-Raman Probe for Cellular Imaging. Cells (2021).