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Extending microsecond time-resolved cryo-electron microscopy with laser flash melting

Nature Reviews Molecular Cell Biology (2026)Cite this article

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Since the resolution revolution, which enabled the high-resolution structure determination of proteins, cryo-electron microscopy (cryo-EM) has become the method of choice for structural biologists. Yet, despite its remarkable capabilities, cryo-EM largely provides static snapshots of biomolecules, which lack dynamic information of biological processes that often occur on the microsecond timescale. Conventional plunge freezing is far too slow to capture these dynamics, creating a major gap in our ability to observe proteins at work.

To address these challenges, we recently expanded our laser-based approach by sealing cryo-EM samples between two ultrathin, vapor-deposited silicon dioxide membranes. The membranes stabilize this liquid sample layer under laser irradiation, extending the accessible observation window by more than an order of magnitude while preserving near-atomic spatial resolution. Beyond enabling microsecond dynamics, the sealed geometry also eliminates the air–water interface, naturally overcoming the long-standing problem of preferred particle orientation, in which proteins adopt only a limited number of views. This restriction limits data collection from all angles and can make it difficult, or in some cases impossible, to obtain high-resolution three-dimensional reconstructions. The approach complements earlier work by our lab showing that laser flash melting can scramble particle orientations by transiently freeing proteins from surface constraints.

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  1. Institute of Chemical Sciences and Engineering – ISIC, EPFL, Lausanne, Switzerland

    Constantin R. Krüger

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  1. Constantin R. Krüger
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Correspondence to Constantin R. Krüger.

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A patent has been filed in relation to this article: patent application US 63/767,702 “High-resolution liquid cells for microsecond time-resolved cryo-EM” filed on 12 March 2025. The author plans to incorporate a company called Alpion CryoSolutions, with the intention of selling instruments that allow the type of experiments mentioned in this piece.

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Krüger, C.R. Extending microsecond time-resolved cryo-electron microscopy with laser flash melting. Nat Rev Mol Cell Biol (2026). https://doi.org/10.1038/s41580-026-00953-5

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  • DOI: https://doi.org/10.1038/s41580-026-00953-5

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