Progress and challenges in traceless ligand-directed labelling chemistry

Abstract Traceless ligand-directed labelling (t-LDL) of proteins is emerging as a potential strategy for addressing the challenge of studying biology within native cellular contexts. By exploiting proximity-driven reactivity, t-LDL enables the selective transfer of small functional groups to residues distal to canonical binding or active sites, allowing the delivery ligand to dissociate following labelling. This review summarises the development of t-LDL chemistry, with a focus on transfer and catalyst-tethered approaches. It highlights key recent advances that expand the mechanistic and functional scope of t-LDL alongside outstanding challenges and opportunities for further development. Examples of applications in live-cell imaging, proteomics, proximity-induced post-translational modification and signalling rewiring, showcase the growing opportunities of this labelling technology.