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

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.