Sensing Single Molecule under Micro-Manipulation (SSM3) was an approach which integrated with single-molecule manipulation and dynamic sensing. This unique technique allows for rapid and ultrasensitive detection of biomarkers beyond the concentration and thermodynamic limits. Currently we are focus on developing the ability of high throughput and multiplexing sensing for the analysis of clinical samples.

Cancer-derived sEVs are regarded as a promising biomarker for liquid biopsy. One of the main challenges in sEV analysis is owing to the heterogeneity at the different dimensions. Conventional cancer diagnostic approach using the ensemble measurement of full sEV population without heterogeneity information would inevitably suffer from the large background noise from irrelevant subpopulations. We present the protein profiling of sEV at the subpopulation level (PPES) by the multiparametric plasmonic detection of sEVs at the single particle level with 30 min. Combining with machine learning algorithm, this method provides a higher accuracy for the classification of five cancers. This approach could further analyze the contents and surface protein markers of sEV, and may contribute to the accurate cancer diagnosis in clinical applications.

We design a rotating illumination module with a pair of high-speed scanning mirrors as the core to achieve fast and accurate control of the incident light azimuth and incidence angle; develop an amplifying lens set and CMOS high-speed imaging device, and build a synchronization control and data acquisition module to achieve simultaneous real-time acquisition of interference images during the rotating illumination process; and further, design an electrochemical module for electrochemical synchronization control and image acquisition to achieve isotropic super resolution interferometric plasmonic microscope, ISR-IPM. Algorithmic advantages： Develop the system transfer function theoretical analysis and improve the spatial resolution based on amplitude and phase analysis of scattered light; Develop a rotating interferometric imaging technique to perform amplitude and phase detection of scattered light in high-speed azimuthal angle-variation imaging  modality; Achieving the goal that spatial resolution is better than 120nm based on the new isotropic imaging technique.

As a new development of surface plasmon resonance microscopy, this chip has many exciting new features and phenomena. The multi-mode excitation mode allows it to have adjustable and controllable resonance state. The basic theoretical analysis enables us to have insight into the novel imaging mode in the microscopic state; The technology can reduce the resonance angle of plasmon resonance significantly, as a result, it is possible to characterize the micro-nano morphology of the sensor chip surface by using the first derivative extreme points of angle spectrum as the parameter, which provides a powerful tool for the real-time non-contact characterization of the surface film morphology; With the help of the powerful enhancement of surface electromagnetic field, the signal-to-noise ratio of nanoparticles is almost an order of magnitude higher than that in its mode, which means that the technology may see more tiny biological particles, which may reveal the mechanism of more micro-nano physiological action that has not been found.