Glycocalyx Imaging Breakthrough Reveals Sugar Structure

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A collaborative workforce 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 organic imaging by visualizing the sugar molecules that coat each human cell at Ångström decision. Their research, now printed in Nature Nanotechnology, demonstrates the primary optical imaging of particular person monosaccharides of their native mobile context, revealing the spatial structure of the glycocalyx with molecular decision.

The glycocalyx is a dense mesh of glycans (sugar chains) adorning cell surfaces, critically concerned in immune signaling, an infection, and most cancers. Despite its significance, its exact nanoscale group has lengthy remained elusive because of the restricted spatial decision of current instruments. Now, utilizing a strong mixture of metabolic labeling and Ångström-resolution fluorescence microscopy, the workforce has overcome this long-standing barrier.

Central to the breakthrough is the RESI (Resolution Enhancement by Sequential Imaging) approach, beforehand developed by the Jungmann lab. RESI achieves Ångström-level spatial decision by temporally separating densely packed molecular targets utilizing distinctive DNA barcodes and sequential imaging. In the brand new research, RESI is paired with metabolic labeling of particular person sugars through bioorthogonal click on chemistry to allow selective, high-efficiency tagging of particular sugar residues akin to sialic acids and LacNAc models immediately 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 creator Ralf Jungmann. “This unlocks a completely new way to study glycosylation in health and disease.”

The researchers utilized RESI to human endothelial cells and efficiently visualized sugar molecules separated by as little as 9 Ångström, roughly the diameter of a single water molecule. They uncovered distinct nanoscale patterns, or “glycan fingerprints,” in line with branched glycan constructions. Statistical evaluation additional revealed how completely different sugars cluster on the cell floor, offering new insights into glycan biosynthesis and group.

“These measurements mark the first time that molecular features of glycans have been resolved in intact cells using light microscopy,” provides Luciano Masullo, co-first creator of the research. “It’s a resolution leap more than 250 times beyond the diffraction limit of light.”

But this isn’t solely a powerful technological achievement, the research opens avenues for understanding how glycan constructions change throughout illness processes akin to most cancers, autoimmune issues, and infections. In explicit, the flexibility to tell apart refined alterations in glycan structure could someday function a diagnostic software or therapeutic guidepost. Because the method is appropriate with massive imaging fields and entire cells, RESI may function a molecular lens via which mobile 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 purposes combining RESI with expanded DNA barcoding and multiplexed protein labeling to concurrently visualize receptors and their connected glycan constructions. Such molecularly resolved maps may illuminate how glycan-receptor interactions govern mobile communication, pathogen recognition, and immune evasion.

Reference: Masullo LA, Almahayni Okay, 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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