The discovery of glycoRNAs—RNAs covalently conjugated to complex glycans—is a transformative development that establishes a new class of epitranscriptomic modifications, challenging the longstanding perception that glycosylation is restricted to proteins and lipids. This rapidly advancing field has seen methodological evolution from early-stage metabolic labeling and click chemistry to highly selective enrichment techniques, such as SPCgRNA (for N-glycoRNAs) and TnORNA (for O-glycoRNAs), and now leverages breakthroughs in spatial and single-cell analysis—such as ARPLA for single cells, drFRET for small extracellular vesicles (sEVs), and SUGAR-seq for multi-omics integration—to allow for high-resolution profiling alongside the transcriptome and proteome. Structurally, the covalent attachment of N-glycans to the modified uridine acp3U on tRNAs has been confirmed, while O-glycans constitute a major and heterogeneous component of the glycoRNA landscape; functionally, glycoRNAs are emerging as critical regulators in immunology and disease, mediating processes like neutrophil recruitment via surface display and acting as ligands for receptors like P-selectin (SELP) and Siglec-5. They also exhibit a dual role in innate immunity, both triggering immune responses and providing N-glycan "shielding" to prevent the aberrant activation of innate immune sensors like TLR3 and TLR7. Despite these foundational discoveries, challenges persist, including resolving interference from glycoprotein signals and developing a universal O-glycan endoglycosidase; however, given their extracellular location, strong correlation with disease, and promising clinical performance, glycoRNAs hold significant potential as highly accurate diagnostic biomarkers and macromolecular therapeutic targets in oncology, cardiovascular disease, and inflammation.
Miao et al. (Sun,) studied this question.