In biology, the connection of atoms and molecules has been long achieved by enzymes with nature demonstrating an unmatched precision and efficiency (e.g. proteases, ligases, etc.). In chemistry, this virtue has fallen onto click reactions, which have profoundly changed the landscape of chemical ligations. Throughout the last decades, click reactions have served way beyond the creation of small molecules, but enabled synthesis and complex functionalization of polymers, 4,5 materials, surfaces, or bio-based substrates, such as peptides, enzymes, and proteins. The majority of click reactions can be broadly classified into two categories: cycloadditions (1,3dipolar, hetero Diels-Alder, etc.), and addition(elimination) reactions between electrophiles and nucleophiles (e.g. active ester chemistry, thio-Michael additions, isocyanate additions, etc.). For the preparation of bioconjugates, amino acids like cysteine, serine or lysine are attractive target groups, with lysine exhibiting both the highest nucleophilicity and average surface accessibility on larger peptides and proteins. Consequently, the substrate of interest can be coupled directly and without further modification to the amino acids on the peptide or protein making addition(-elimination) reactions an attractive strategy for the generation of bioconjugates and biohybrid materials. Regarding the electrophiles, acyl chlorides, NHS-esters, and perfluorinated phenyl ester have been used, however, such active esters commonly release a leaving group, which ultimately has to be removed from the reaction product. Electrophiles that undergo addition reactions (without formation of by-products) are therefore preferable, yet, highly reactive reagents, such as isocyanates, find limited use in aqueous media where they can be rapidly hydrolyzed. As a third factor, multicomponent reactions have become increasingly popular, as they allow to modularly modify respective substrates in a cascade reaction, whose reaction trajectory is dictated by the reactions present in solution. The reactive groups known as thiolactones (TL) combine all three characteristics: they undergo an addition reaction, selectively ring-open in the presence of amines and their unique heterocyclic structure allows to couple multiple substrates at once in a multicomponent reaction. In a single modification, the heterocyclic carbonyl undergoes chemo-and regio-selective amidation (Figure ). In the presence of both an amine and a Michael acceptor (e.g. maleimide), a three-component reaction takes place, which is often termed double modification (ring-opening followed by thiol-X reaction). On the basis of this unique reactivity, TLs have been extensively used for postpolymerization modification, towards sequencedefined and functional polymers , surfaces, hydrogels, as well as bioconjugates / biohybrid materials. In one of our previous studies, it was demonstrated that an epoxy-functional TL can undergo aminetriggered thiol-epoxy polymerization. When amino acids and smaller peptides were attached to the TL in the presence of base, polypeptides/polyelectrolytes were formed in a facile one-pot procedure. Only recently, Jiang et al. demonstrated improved bioconjugation of amino acids to TL in the presence Ag(I) ions and 1,4-diazabicyclo[2.2.2]octane (DABCO). In another example, the polysaccharide pullulan was furnished with intact TLs to undergo peptide-triggered gelation. The resulting hydrogels were successfully tethered with cell-signaling peptides and promoted cell growth and proliferation. A similar concept was realized by Heinze and co-workers, who functionalized dextrane with TLs to allow for an easily adaptable polysaccharide modification. As opposed to aliphatic amines, however, amine-containing biological substrates, such as gelatin, other proteins, and enzymes exhibit much lower nucleophilicity, limiting the TL functionalization severely for applications in the field of bioconjugate materials.