Document Type

Article

Publication Date

1-18-2026

Keywords

Bioorthogonal cleavage, Click to release, Host-guest systems, Noncovalent click chemistry, Host-guest systems, Noncovalent click chemistry, Self–immolative chemistry

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.

Comments

https://doi.org/10.1002/anie.202515594

Publisher Attribution

© 2026 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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