Can we read a molecular sequence directly from its chemical fingerprints? Raman spectroscopy offers a compelling route: its ability to distinguish chemical groups could enable the identification of nucleotides, amino acids, and their modifications within a single sensing platform. The challenge is to capture these fingerprints as individual molecules move through a nanoscale detection region.

In this seminar, I will present our approach to Raman sequential readout, which combines nanopore-inspired molecular transport with surface-enhanced Raman scattering. Scalable, plasmonic nanopore guide molecules electrophoretically through ultrasmall optical hotspots, where their Raman spectra are recorded in real time. Strong light–matter coupling and extreme optical field confinement enable spatial resolution on the order of a few angstroms. By integrating single-photon avalanche diode (SPAD) cameras, we achieve acquisition times of just 10 microseconds at a continuous frame rate of 100 kHz, opening access to fleeting molecular events.

We have captured single-molecule Raman fingerprints of the four DNA nucleotides and multiple amino acids, achieving 89% discrimination accuracy for nucleotides. These results establish key capabilities toward sequencing through successive chemical fingerprints. I will discuss the opportunities and remaining challenges in extending this approach to DNA, RNA, and proteins, with the prospect of identifying not only molecular sequences but also the chemical modifications that shape their biological function.