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  • Technical Review
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Cryogenic electron microscopy and tomography for beam-sensitive materials

Nature Reviews Physics volume 8, pages 40–54 (2026)Cite this article

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Abstract

In the life sciences, cryogenic electron microscopy (cryo-EM) has revolutionized structure determination by providing atomic-resolution structures of biomolecules in their native environment and in multiple conformational states. The applications of cryo-EM techniques have been extended from structural biology, which mainly focuses on structural information, to materials science, where chemical and physical information are equally important. In this Technical Review, we focus on sample preparation methods and imaging strategies to enable high-resolution imaging of beam-sensitive materials while avoiding electron-beam damage. We also survey emerging methods and applications, with an emphasis on energy materials.

Key points

  • Effective sample preparation is crucial for maintaining the native state of materials and preventing phase transitions or chemical reactions during imaging.

  • Advanced fast freezing techniques have demonstrated the potential of cryo-electron microscopy (cryo-EM) to capture intermediate states in energy-related processes by slowing or halting these processes at cryogenic temperatures. Applying external fields (electric, magnetic or light) during freezing could allow for even more precise control over these states.

  • The effect of electron radiation damage on cryo-EM imaging and spectroscopy can be mitigated by minimizing the beam dose using low-dose techniques, maximizing the signal-to-noise ratio with a direct electron detector, and optimizing imaging conditions based on specific material type and properties of the sample.

  • Analytical scanning transmission electron microscopy (STEM) techniques such as energy-dispersive X-ray spectroscopy and electron energy-loss spectroscopy at cryogenic temperatures, along with 4D-STEM and ptychography for detailed structural mapping, greatly expand the utility of cryo-EM in materials science.

  • The development of cryo-electron tomography and advanced data and image processing methods has further enabled 3D imaging and analysis of materials, opening new avenues for studying complex materials systems.

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Fig. 1: Example protocols for sample preparation for cryo-electron microscopy.
Fig. 2: High-resolution imaging of beam-sensitive materials using low-dose cryo-EM.
Fig. 3: Examples of cryo-STEM applications in materials research.
Fig. 4: Cryo-electron tomography.

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Acknowledgements

The authors acknowledge cryo-EM FWP support from the Office of Basic Energy Sciences, US Department of Energy, Division of Materials Science and Engineering, DE-AC02-76SF00515.

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  1. These authors contributed equally: Yi Cui 崔一, Zewen Zhang.

Authors and Affiliations

  1. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA

    Yi Cui  (崔一), Zewen Zhang, Robert Sinclair & Yi Cui  (崔屹)

  2. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Wah Chiu

  3. Stanford Institute for Materials and Energy Sciences, SLAC National Accelerator Laboratory, Menlo Park, CA, USA

    Yi Cui  (崔屹)

  4. Department of Energy Science and Engineering, Stanford University, Stanford, CA, USA

    Yi Cui  (崔屹)

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  1. Yi Cui  (崔一)
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Cui, Y., Zhang, Z., Sinclair, R. et al. Cryogenic electron microscopy and tomography for beam-sensitive materials. Nat Rev Phys 8, 40–54 (2026). https://doi.org/10.1038/s42254-025-00896-4

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