In transmission electron microscopy (TEM), because electrons interact strongly with matter, resolution is limited by the thickness of the sample. Also, the thickness of the sample increases as the sample is tilted, and thicker samples can then completely block the electron beam, making the image dark or completely black. Therefore, for CryoET, samples should be less than ~500 nm thick to achieve "macromolecular" resolution (~4 nm). For this reason, most ECT studies have focused on purified macromolecular complexes, viruses, or small cells such as those of many species of Bacteria and Archaea. Cryotomography was used to understand encapsulation of 12 nm size protein cage nanoparticles inside 60 nm sized virus-like nanoparticles.
