The emergence of super-resolution (SR) fluorescence microscopy has rejuvenated the search for new cellular sub-structures. However, SR fluorescence microscopy achieves high contrast at the cost of the lack of a holistic view of their interacting partners and surrounding environment. Thus we develop SR fluorescence-assisted diffraction computational tomography (SR-FACT), which combines label-free three-dimensional optical diffraction tomography (ODT) with two-dimensional fluorescence Hessian structured illumination microscopy. The ODT module is capable of resolving mitochondria, lipid droplets, the nuclear membrane, chromosomes, the tubular endoplasmic reticulum and lysosomes. Using dual-mode correlated live cell imaging for prolonged period of time, we observe the dynamics of a novel subcellular structure named dark-vacuole bodies. These works demonstrate the unique capabilities of SR-FACT, which suggest its wide applicability in cell biology in general.
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