Xiaowei Xu, Xidan Tong, Yangfei Shi, Xin Wang, Yanzhao Chen, Y. Wang, Mingxin Cheng, Shuanglong Chen, Hao Hao, Yan Liang, Weiwei Guo, Yueqin Zheng
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. The advancement of bioorthogonal bond-breaking chemistry requires precise spatiotemporal control over chemical reactions. Here, the authors introduce a stimuli-responsive click–release platform based on the reaction between mono-alkylhydroxylamine and cyclooctyne, enabling rapid and nearly complete payload release, and apply it to release of anticancer drugs and anaesthetics.