Label-Free Tracking of Proteins through Plasmon-Enhanced Interference

Single unmodified biomolecules in solution can be observed and characterized by interferometric imaging approaches; however, Rayleigh scattering limits this to larger proteins (typically >30 kDa). We observe real-time image tracking of unmodified proteins down to 14 kDa using interference imaging enhanced by surface plasmons launched at an aperture in a metal film. The larger proteins show slower diffusion, quantified by tracking. When the diffusing protein is finally trapped by the nanoaperture, we perform complementary power spectral density and noise amplitude analysis, which gives information about the protein. This approach allows for rapid protein characterization with minimal sample preparation and opens the door to characterizing protein interactions in real time.