A Noncovalent Click‐to‐Release Strategy to Control Bond Cleavage and Prodrug Activation

Abstract

Abstract Click‐to‐release chemistry enables bioorthogonal bond cleavage and controlled release via a click‐type ligation reaction serving as both the trigger and means of localization. Extending this concept beyond covalent ligation reactions, we introduce a noncovalent click‐to‐release strategy based on cucurbit[7]uril‐adamantane (CB‐Ad) association. The CB host molecule forms a pre‐assembled host‐guest complex with a self‐immolative guest (SIG) SIG1, where the masked SIG remains inert. Introduction of a high‐affinity guest Ad initiates the CB‐Ad noncovalent click reaction, displacing SIG1 and triggering its self‐immolation and cargo release. As a proof‐of‐concept, we used a prototype prodrug SIG2 to demonstrate our strategy's potential for controlled therapeutic release, effectively regulating the photodynamic cell killing in vitro. This noncovalent click‐to‐release approach broadens the structural and functional scope of bioorthogonal cleavage strategies with promising implications for stimuli‐responsive materials and biomedical applications.