Structural biology has changed our understanding of life on the atomic scale. However, we still do not understand how molecules in the context of an organism carry out their functions well enough to understand how to treat complex diseases. Recent efforts to turn structural biology into a technique capable of looking at the structure of molecule within cells have led to a step change in approach and has led to an atomic scale understanding of molecules within tissues. However, for tissues, all-sample mapping under cryogenic conditions is still not possible meaning expanding the applications of structural cell biology to distinct processes in tissues is lacking. Current scanning electron microscopes (SEM) are optimised for tissue that has been fixed, resin-embedded and stained with heavy metals, where the requirement for charge mitigation and image optimisation for high resolution imaging is less challenging. In contrast, samples that have been vitrified for structural studies downstream are fully hydrated, and exhibit a high degree of image artefacts due to the remaining water content. The ability to image these samples with their native frozen-hydrated environment intact is still challenging, and requires new image acquisition methods to embed them as a routine tool for correlative multimodal imaging. As part of this proposal, we aim to optimise SEM imaging in our recently published multimodal workflow by implementing sparse and irregular optimised scanning routines to overcome the charge build up that occurs with standard imaging regimes. Our preliminary development work shows that such an approach can make a significant difference in the image quality of natively preserved cells and tissues, on an instrument which is integral to a structural biology workflow. This represents a step-change, where features of high relevance can be targeted, imaged with high fidelity and processed for subsequent analysis. Such an instrument will represent a transformative ability to image molecular processes in tissues, facilitating efforts to combat neurodegeneration, cardiomyopathies, liver disease and kidney dysfunction.