Accessing new dimensions in high-resolution materials exploration by cryo-electron microscopy

Cryo-electron microscopy (cryo-EM) is employed for structural analyses, visualizing high-resolution information across scales, i.e., from tissues to small molecules. Developments allowing near-atomic resolution cryo-EM imaging of biological macromolecules were recognized by the 2017 Nobel Prize in Chemistry. In the materials science domain, despite specific applications, cryo-EM analysis presents discrete challenges related to sample preparation, imaging, and data interpretation, as function of the sample’s innate physical chemistry. Here, we review recent progress in the field, focusing on overcoming intricacies in analysis of soft matter ( e.g., polymers, gels, colloids) and functional materials like metal-organic frameworks (MOFs), covalent organic frameworks (COFs), and hybrid perovskites. Sample preparation, including grid selection, surface treatments, and vitrification methods are compared, highlighting their effects on image quality and artifact reduction. Advanced cryo-EM methods, and their combination with scanning transmission electron microscopy (STEM) and low-dose energy loss spectroscopy (EELS) are also examined to evaluate their potential in describing complex molecular structures and their conformational heterogeneity. This review, overall, highlights the need for standardized, statistically empowered cryo-EM protocols inspired from biological applications, and integration of emerging technologies like machine learning and open data initiatives, to ultimately incorporate cryo-EM into materials research as a fundamental method.