Ångström-resolution imaging of cell-surface glycans

Glycobiology is rooted in the study of monosaccharides, ångström-sized molecules that are the building blocks of glycosylation. Glycosylated biomolecules form the glycocalyx, a dense coat encasing every human cell with central relevance-among others-in immunology, oncology and virology. To understand glycosylation function, visualizing its molecular structure is fundamental. However, the ability to visualize the molecular architecture of the glycocalyx has remained challenging. Techniques such as mass spectrometry, electron microscopy and fluorescence microscopy lack the necessary cellular context, specificity and resolution. Here we combine resolution enhancement by sequential imaging with metabolic labelling, enabling the visualization of individual sugars within glycans on the cell surface, thus obtaining images of the glycocalyx with a spatial resolution down to 9 Å in an optical microscope.