Label-free interferometric scattering microscopy and spectroscopy with single-molecule sensitivity

Interferometric scattering microscopy is a breakthrough in ultrasensitive, label-free detection of biomolecules enabled by fast and sensitive imaging of light scattered by weakly scattering objects. Our research focuses on discerning subtle fluctuations in the scattering signal to describe biomolecular interactions and processes hidden deep within the subdiffractional volume of the probe beam. We demonstrate how the fluctuation in the scattering amplitude can be associated with conformation changes taking place at the level of a single, or a few unlabeled biomolecules and open new possibilities for the next generation of super-resolution microscopy techniques. We further combine the ultrasensitive detection of single molecules with real-time Raman spectroscopy to monitor the structural fluctuations on the single-molecule level. Understanding the dynamics of biological matter opens new avenues in label-free super-resolution microscopy and ultimately sensitive detection and identification of biomolecular samples.