Ultrasensitive bright-field microscope enables label-free single-protein detection

We demonstrate that bright-field microscopy, when implemented in a coherent transmission-mode configuration termed coherent brightfield (COBRI) microscopy, achieves exceptional sensitivity sufficient for direct visualization of single proteins without any labels. Through tailored control of illumination coherence, intensity, and interference contrast, we resolve individual protein binding events on coverslips with molecular masses from 150 to 915 kDa, corresponding to scattering cross-sections down to the order of 10^-6 nm². Furthermore, the optical contrast of single proteins scales linearly with molecular polarizability and mass, enabling quantitative detection. These results establish COBRI microscopy as a powerful, accessible platform for label-free single-molecule imaging, affirming the interferometric potential of bright-field optics and extending their utility to biomolecular detection.