Label-free detection of nanoparticles using depth scanning correlation interferometric microscopy

Single particle level visualization of biological nanoparticles such as viruses and exosomes is challenging due to their small size and low dielectric contrast. Fluorescence based methods are highly preferred, however they require labelling which may perturb the functionality of the particle of interest. On the other hand, wide-field interferometric microscopy can be used to detect sub-diffraction limited nanoparticles without using any labels. Here we demonstrate that utilization of defocused images enhances the visibility of nanoparticles in interferometric microscopy and thus improves the detectable size limit. With the proposed method termed as Depth Scanning Correlation (DSC) Interferometric Microscopy, we experimentally demonstrate the detection of sub-35nm dielectric particles without using any labels. Furthermore, we demonstrate direct detection of single exosomes. This label-free and high throughput nanoparticle detection technique can be used to sense and characterize biological particles over a range between a few tens to a few hundred nanometers, where conventional methods are insufficient.