Abstract
The advancement of bioorthogonal bond-breaking chemistry requires precise spatiotemporal control over chemical reactions. In this study, we introduce a click-release strategy based on the reaction between mono-alkyl-hydroxylamine and cyclooctyne (COT), enabling rapid and nearly complete payload release. We demonstrate that mono-alkyl-hydroxylamine and hydroxylamine react with COT to form nitrone and oxime, respectively, facilitating a versatile and efficient release mechanism. By conjugating mono-alkyl-hydroxylamine with responsive cleavable groups, we convert its inherent reactivity into an on-demand activation system. In vivo, this strategy is applied in a 4T1 mouse breast tumor model, showing significant tumor inhibition compared to the parent anticancer drug. Additionally, in local anesthesia, the anesthetic effect could be modulated by light exposure, allowing for repeated activation. This click-release system combines fast kinetics, high release efficiency, and precise spatiotemporal control, offering promising applications in chemical biology and drug delivery.
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All data supporting the findings of this manuscript, including full characterization data for new compounds and detailed experimental procedures, are provided within the main text and Supplementary Information, and are available from the corresponding authors upon request. Source data are provided with this paper.
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Acknowledgements
The authors are gratefully thankful for the support from the National Natural Science Foundation of China, China (22377147 and 22577156), and the Specialized Research Funds from the State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMZZ2024JS38).
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X.X., X.T. and Y.S. contributed equally. Y.Z. and W.G. conceived the initial idea and supervised the study and the overall manuscript preparation and revision process. X.X. designed and performed the experiments and drafted the manuscript. X.X. and X.T. synthesized and characterized the related compounds. X.T. also revised the manuscript. Y.S., X.W., and M.C. conducted studies of the reaction kinetics and some of the synthesis. Y.C. and X.X. conducted the in vitro biology studies. X.X., Y.S., X.W., S.C., and Y.W. evaluated the antitumor and local anesthetic activities. Y.L. designed and supervised the pharmacokinetic studies. Y.S. and H.H. performed the pharmacokinetic studies. All authors reviewed, edited, and approved the final manuscript.
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Xu, X., Tong, X., Shi, Y. et al. Spatiotemporally controlled drug release via a click-release system utilizing mono-alkyl-hydroxylamine and cyclooctyne chemistry. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68502-4
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DOI: https://doi.org/10.1038/s41467-026-68502-4
