Cell-type selective metabolic labeling of glycans in complicated biological environments remains a big challenge. Herein, we develop a glycan labeling tool by encapsulating a non-natural azido sugar (ManNAz) into a mannosyl ligand-modified metal-organic framework (MOF) (MIL-101-Man). The mannosyl ligands multivalently displayed on the surface of the MOFs bind specifically to mannose receptors (MRs) expressed on the surface of a target cell to mediate targeted delivery of the unnatural sugar. Upon endocytosis, exposure of the MOFs to the acidic environment of the endosomes and lysosomes resulted in the release of ManNAz to subsequently undergo metabolic incorporation into cellular glycans. A series of biological experiments followed by fluorescence-based biorthogonal cell labelling demonstrated the receptor-dependent uptake of MIL-101-Man, and an assay involving the co-culture of two cell lines in one cellular medium confirmed the target specificity of the MOFs for the glycoengineering of target cells that overly express MRs over adjacent control cells with minimal MR expression. This study offers an effective tool for the metabolic glycoengineering of cells in a receptor-targeting manner.
Tong et al. (2026) studied this question.