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

## TL;DR

Scientists developed a new noncovalent method to control drug release using a host-guest complex, enabling precise activation of therapeutics.

## Contribution

The novel noncovalent click-to-release strategy uses cucurbit[7]uril-adamantane interactions to control prodrug activation.

## Key findings

- A prototype prodrug demonstrated controlled therapeutic release in vitro using the CB-Ad system.
- The noncovalent strategy enables stimuli-responsive cargo release through supramolecular displacement.
- This approach expands the scope of bioorthogonal cleavage for biomedical and material applications.

## 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.

Extending the click‐to‐release concept beyond covalent ligation, we introduce a noncovalent click‐to‐release strategy based on cucurbituril‐adamantane (CB‐Ad) association. A supramolecular preassembly encapsulating a self‐immolative guest (SIG) is rationally designed to prevent premature release, while adding a high‐affinity Ad guest initiates the CB‐Ad click reaction, displacing the SIG and triggering its preprogrammed cleavage for cargo release.