Integral scattering microscopy of single molecules beyond quantum noise limit

Due to the intrinsically small molecular scattering cross section and quantum noise limit, optical detection of single unlabeled molecules relies on increased optical intensity, leading to limitations in photodamage, sensitivity and space bandwidth. We discovered that integral detection with in-plane scattering of surface plasmon polaritons provides a sensitivity beyond the quantum noise limit. We demonstrate the integral scattering microscopy (InS) with a three orders of magnitude reduction in optical intensity and a two orders of magnitude increase in space bandwidth product, while maintaining state-of-the-art single-molecule sensitivity. InS can be applied in as wide as mass imaging single macromolecules, quantifying dynamics of single-molecule interaction, characterizing cell-secreted supermere, and detecting biomarkers in a multiplexed and label-free manner.