Guest Editorial for the Accounts of Chemical Research special issue “Cryogenic Electron Microscopy”. Developing tools and methodologies to obtain chemical and physical information at atomic resolution has been critical for a broad field of physical sciences, engineering, and life sciences. Electron microscopy has been a powerful tool and has seen recent significant advancements in its resolution in space, energy, and time as well in situ recording of dynamic structural evolution under physical and chemical stimuli. However, molecules, biological systems, and many important materials are highly sensitive to the electron beam, generating significant challenges for atomic scale imaging and chemical information mapping. Cryogenic electron microscopy (cryo-EM) affords an exciting tool to study sensitive systems with atomic resolution. Cryo-EM has revolutionized the life sciences by providing atomic structures of sensitive biomolecules in their native states, which was recognized with the 2017 Chemistry Nobel Prize. The success of cryo-EM was built on the early innovations in fast freezing methods of biomolecules in their hydrated vitreous state, stabilization of biomolecules under the electron beam at cryogenic temperatures, and computational methods to determine their structure. Recent innovations further increasing the power of the cryo-EM tool include more stable specimen stages, aberration correctors, and very importantly direct electron detectors for low-dose imaging. Modern cryo-EM tools and methods have opened up very exciting opportunities beyond life sciences and extended into physical sciences and engineering. As examples, the following important materials and chemical systems would benefit tremendously by exploiting modern cryo-EM tools: (1) Energy storage materials. Batteries store energy through electrochemical reactions with active electron and ion transport. Therefore, battery electrode materials are highly dynamic, but many are very sensitive to the electron beam. In lithium ion batteries, an interfacial layer called the solid–electrolyte interphase (SEI) is often formed between electrode materials and the liquid electrolyte, which affects the battery electrochemical performance. Recent studies on atomic-scale imaging of lithium metal anode and its SEI structure show the great promise of the cryo-EM technique for battery research. Hydrogen storage material is another example, where cryogenic temperature slows down the hydrogen reaction kinetics to the time scale possible to capture in an electron microscope. (2) Soft materials: molecules and polymers. Similar to biomolecules, small molecules and polymers are highly sensitive to an electron beam. Correlating their molecular structure and chemistry with physical properties is important for both fundamental understanding and engineering design in applications such as organic electronics and solid polymer electrolytes. Recent studies with four-dimensional scanning transmission electron microscopy (4D-STEM) and STEM–electron energy loss spectroscopy (EELS) under cryogenic conditions represent exciting advancement for these materials. (3) Metal–organic frameworks (MOFs) and covalent organic frameworks (COFs). MOFs are a large class of porous materials constructed with the principle of metal sites linked by organic ligands three-dimensionally. They have been shown to have potential applications in gas storage, separation, catalysis, and energy storage. Interactions between the host frameworks and guest molecules are central to such applications, but atomic imaging is a big challenge due to their high sensitivity to the electron beam. COFs have similar applications and are also very sensitive materials. Cryo-EM has started to show its power in imaging CO₂ molecules in the MOF structure under low-dose conditions, opening up the opportunity for high resolution imaging of the large family of MOFs and COFs. (4) Hybrid organic–inorganic halide perovskites. The hybrid perovskites are an exciting family of optoelectronic materials for solar cells and light emission applications. However, they are sensitive to physical stimuli such as light, the electron beam, and environmental exposure (e.g., moisture), making it very challenging to obtain atomic resolution imaging. The cryo-sample transfer technique without air exposure and cryo-EM imaging under low-dose conditions afford the possibility to address these challenges. (5) Quantum materials. Quantum materials exhibit interesting quantum phase transitions that often occur at low temperatures and involve electron, spin, or lattice order from the atomic to mesoscopic scales. The complex interplay of these states and the heterogeneity that arises due to competition and intertwining of phases, however, is not fully understood and requires probes that capture ordering over multiple length scales down to local atomic symmetries. Advances in scanning transmission electron microscopy (STEM) have enabled atomic-resolution imaging as well as mapping of functional picometer-scale atomic displacements inside materials. The modern cryo-EM tools are powerful options to study myriad chemical and materials systems. However, new technique developments are still needed. Several important areas are highlighted here. First, sample preparation techniques are needed. How to freeze samples into their intrinsic state during device operation is an exciting challenge. How to thin down the samples without damaging their intrinsic states is another one. Second, developing a stable sample holder down to liquid helium temperature or lower is a big challenge, particularly for studying quantum materials. Third, advances in imaging conditions and data processing are still needed. The cryo-EM field will benefit tremendously from utilizing artificial intelligence methods. Fourth, how to obtain in-operando dynamic structure information and to capture the metastable states is an exciting frontier in cryo-EM. In this special issue of Accounts of Chemical Research, we have organized leading research groups to address the exciting opportunities and challenges in this fast growth field of science. This article has not yet been cited by other publications.

中文翻译：

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使用低温电子显微镜对敏感材料、界面和量子材料进行成像

化学研究账户的客座编辑特刊“低温电子显微镜”。开发以原子分辨率获取化学和物理信息的工具和方法对于物理科学、工程和生命科学的广泛领域至关重要。电子显微镜一直是一种强大的工具，最近在空间、能量和时间分辨率以及物理和化学刺激下动态结构演化的原位记录方面取得了重大进展。然而，分子、生物系统和许多重要材料对电子束高度敏感，给原子尺度成像和化学信息映射带来了重大挑战。低温电子显微镜 (cryo-EM) 提供了一种令人兴奋的工具来研究具有原子分辨率的敏感系统。冷冻电镜通过提供原始状态下敏感生物分子的原子结构，彻底改变了生命科学，并获得了 2017 年诺贝尔化学奖。冷冻电镜的成功建立在早期创新的基础上，即水合玻璃体状态下生物分子的快速冷冻方法、低温电子束下生物分子的稳定性以及确定其结构的计算方法。最近的创新进一步提高了冷冻电镜工具的功能，包括更稳定的样品台、像差校正器，以及非常重要的用于低剂量成像的直接电子探测器。现代冷冻电镜工具和方法为生命科学以外的领域开辟了非常令人兴奋的机会，并扩展到物理科学和工程领域。作为例子，储能材料。电池通过具有活性电子和离子传输的电化学反应来储存能量。因此，电池电极材料是高度动态的，但许多对电子束非常敏感。在锂离子电池中，电极材料和液体电解质之间通常会形成称为固体电解质界面（SEI）的界面层，这会影响电池的电化学性能。最近对锂金属负极及其 SEI 结构的原子级成像的研究表明，冷冻电镜技术在电池研究中具有广阔的前景。储氢材料是另一个例子，其中低温将氢反应动力学减慢到电子显微镜可能捕获的时间尺度。(2)软材料：分子和聚合物。与生物分子类似，小分子和聚合物对电子束高度敏感。将它们的分子结构和化学与物理性质相关联，对于有机电子和固体聚合物电解质等应用中的基本理解和工程设计都很重要。最近在低温条件下使用四维扫描透射电子显微镜 (4D-STEM) 和 STEM-电子能量损失谱 (EELS) 进行的研究代表了这些材料令人兴奋的进步。(3)金属有机骨架（MOFs）和共价有机骨架（COFs）. MOFs是一大类多孔材料，其原理是金属位点通过有机配体三维连接。它们已被证明在气体储存、分离、催化和能量储存方面具有潜在应用。主体框架和客体分子之间的相互作用是此类应用的核心，但原子成像因其对电子束的高灵敏度而成为一大挑战。COFs 有类似的应用，也是非常敏感的材料。Cryo-EM 已开始显示其在低剂量条件下对 MOF 结构中的CO ₂分子成像的能力，为大家族 MOF 和 COF 的高分辨率成像开辟了机会。(4)杂化有机-无机卤化物钙钛矿。混合钙钛矿是用于太阳能电池和发光应用的一系列令人兴奋的光电材料。然而，它们对光、电子束和环境暴露（例如，湿气）等物理刺激很敏感，这使得获得原子分辨率成像非常具有挑战性。无空气暴露的低温样品转移技术和低剂量条件下的低温 EM 成像提供了解决这些挑战的可能性。(5)量子材料。量子材料表现出有趣的量子相变，这些相变通常发生在低温下，涉及从原子到介观尺度的电子、自旋或晶格顺序。然而，这些状态的复杂相互作用以及由于相的竞争和交织而产生的异质性尚未完全理解，并且需要能够捕获多个长度尺度上的排序到局部原子对称性的探针。扫描透射电子显微镜 (STEM) 的进步使原子分辨率成像以及材料内部功能性皮米级原子位移的映射成为可能。现代冷冻电镜工具是研究无数化学和材料系统的强大选择。然而，仍然需要新技术的发展。这里突出显示了几个重要领域。第一的，需要样品制备技术。如何在设备运行期间将样品冷冻到其固有状态是一个令人兴奋的挑战。如何在不破坏其固有状态的情况下减薄样品是另一回事。其次，开发稳定的样品架低至液氦温度或更低是一个很大的挑战，特别是对于研究量子材料。第三，成像条件和数据处理仍需进步。冷冻电镜领域将从利用人工智能方法中受益匪浅。第四，如何获得操作中动态结构信息并捕获亚稳态是冷冻电镜的一个令人兴奋的前沿。在本期特刊中 如何在不破坏其固有状态的情况下减薄样品是另一回事。其次，开发稳定的样品架低至液氦温度或更低是一个很大的挑战，特别是对于研究量子材料。第三，成像条件和数据处理仍需进步。冷冻电镜领域将从利用人工智能方法中受益匪浅。第四，如何获得操作中动态结构信息并捕获亚稳态是冷冻电镜的一个令人兴奋的前沿领域。在本期特刊中 如何在不破坏其固有状态的情况下减薄样品是另一回事。其次，开发稳定的样品架低至液氦温度或更低是一个很大的挑战，特别是对于研究量子材料。第三，成像条件和数据处理仍需进步。冷冻电镜领域将从利用人工智能方法中受益匪浅。第四，如何获得操作中动态结构信息并捕获亚稳态是冷冻电镜的一个令人兴奋的前沿领域。在本期特刊中 冷冻电镜领域将从利用人工智能方法中受益匪浅。第四，如何获得操作中动态结构信息并捕获亚稳态是冷冻电镜的一个令人兴奋的前沿领域。在本期特刊中 冷冻电镜领域将从利用人工智能方法中受益匪浅。第四，如何获得操作中动态结构信息并捕获亚稳态是冷冻电镜的一个令人兴奋的前沿领域。在本期特刊中Accounts of Chemical Research，我们组织了领先的研究小组来应对这个快速增长的科学领域中令人兴奋的机遇和挑战。这篇文章还没有被其他出版物引用。