Scattering-based light microscopy: From metal nanoparticles to single proteins

Our ability to detect, image, and quantify nanoscopic objects and molecules with visible light has undergone dramatic improvements over the past few decades. While fluorescence has historically been the go-to contrast mechanism for ultrasensitive light microscopy due to its superior background suppression and specificity, recent developments based on light scattering have reached single-molecule sensitivity. They also have the advantages of universal applicability and the ability to obtain information about the species of interest beyond its presence and location. Many of the recent advances are driven by novel approaches to illumination, detection, and background suppression, all aimed at isolating and maximizing the signal of interest. Here, we review these developments grouped according to the basic principles used, namely darkfield imaging, interferometric detection, and surface plasmon resonance microscopy