Visualizing the Glycocalyx – the Sugar Molecules That Coat Human Cells
New research has visualized the sugar molecules that coat every human cell at Ångström resolution.
A collaborative team led by Ralf Jungmann (Max Planck Institute of Biochemistry and LMU Munich) and Leonhard Möckl (Max Planck Institute for the Science of Light and FAU Erlangen-Nürnberg) has pushed the boundaries of biological imaging by visualizing the sugar molecules that coat every human cell at Ångström resolution. Their study, now published in Nature Nanotechnology, demonstrates the first optical imaging of individual monosaccharides in their native cellular context, revealing the spatial architecture of the glycocalyx with molecular resolution.
The glycocalyx is a dense mesh of glycans (sugar chains) decorating cell surfaces, critically involved in immune signaling, infection, and cancer. Despite its importance, its precise nanoscale organization has long remained elusive due to the limited spatial resolution of existing tools. Now, using a powerful combination of metabolic labeling and Ångström-resolution fluorescence microscopy, the team has overcome this long-standing barrier.
Central to the breakthrough is the RESI (Resolution Enhancement by Sequential Imaging) technique, previously developed by the Jungmann lab. RESI achieves Ångström-level spatial resolution by temporally separating densely packed molecular targets using unique DNA barcodes and sequential imaging. In the new study, RESI is paired with metabolic labeling of individual sugars via bioorthogonal click chemistry to enable selective, high-efficiency tagging of specific sugar residues such as sialic acids and LacNAc units directly on intact cells.
“By resolving the glycocalyx sugar-by-sugar, we can now map structural patterns at a scale that was previously invisible,” says co-senior author Ralf Jungmann. “This unlocks a completely new way to study glycosylation in health and disease.”
The researchers applied RESI to human endothelial cells and successfully visualized sugar molecules separated by as little as 9 Ångström, approximately the diameter of a single water molecule. They uncovered distinct nanoscale patterns, or “glycan fingerprints,” consistent with branched glycan structures. Statistical analysis further revealed how different sugars cluster on the cell surface, providing new insights into glycan biosynthesis and organization.
“These measurements mark the first time that molecular features of glycans have been resolved in intact cells using light microscopy,” adds Luciano Masullo, co-first author of the study. “It’s a resolution leap more than 250 times beyond the diffraction limit of light.”
But this is not only an impressive technological achievement, the study opens avenues for understanding how glycan structures change during disease processes such as cancer, autoimmune disorders, and infections. In particular, the ability to distinguish subtle alterations in glycan architecture may one day serve as a diagnostic tool or therapeutic guidepost. Because the approach is compatible with large imaging fields and whole cells, RESI could serve as a molecular lens through which cellular glycosylation is studied at scale.
“This work shifts the bottleneck in glycocalyx research from spatial resolution to labeling,” explains Ralf Jungmann. “With further improvements in sugar labeling chemistry, RESI could allow full structural glycan mapping and possibly glycoproteomics via optical methods.”
The researchers envision future applications combining RESI with expanded DNA barcoding and multiplexed protein labeling to simultaneously visualize receptors and their attached glycan structures. Such molecularly resolved maps could illuminate how glycan-receptor interactions govern cellular communication, pathogen recognition, and immune evasion.
Reference: Masullo LA, Almahayni K, Pachmayr I, et al. Ångström-resolution imaging of cell-surface glycans. Nat Nanotechnol. 2025. doi: 10.1038/s41565-025-01966-5
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