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Review
. 2025 May;45(3):887-908.
doi: 10.1002/med.22095. Epub 2024 Dec 18.

Advances in the Delivery, Activation and Therapeutics Applications of Bioorthogonal Prodrugs

Zhou Zhou  1 , Yuanjun Sun  1   2 , Jing Pang  1   2 , Ya-Qiu Long  1   2
Affiliations
Review

Advances in the Delivery, Activation and Therapeutics Applications of Bioorthogonal Prodrugs

Zhou Zhou et al. Med Res Rev. 2025 May.

Abstract

Traditional prodrug strategies have been leveraged to overcome many inherent drawbacks of active native drugs in the drug research and development. However, endogenous stimuli such as specific microenvironment or enzymes are relied on to achieve the prodrug activation, resulting in unintended drug release and systemic toxicity. Alternatively, bioorthogonal cleavage reaction-enabled bioorthogonal prodrugs activation via exogenous triggers has emerged as a valuable approach, featuring spatiotemporally controlled drug release. Such bioorthogonal prodrug strategies would ensure targeted drug delivery and/or in situ generation, further circumventing systemic toxicity or premature elimination of active drugs. In recent years, metal-free bioorthogonal cleavage reactions with fast kinetics have boomed in the bioorthogonal prodrug design. Meanwhile, transition-metal-catalyzed and photocatalytic deprotection reactions have also been developed to trigger prodrug activation in biological systems. Besides traditional small molecule prodrugs, gasotransmitters have been successfully delivered to specific organelles or cells via bioorthogonal reactions, and nanosystems have been devised into bioorthogonal triggers as well. Herein, we present an overview of the latest advances in these bioorthogonally-uncaged prodrugs, focused on the delivery, activation and therapeutics applications.

Keywords: bioorthogonal chemistry; prodrug activation; spatiotemporal control; targeted delivery; theranostics.

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