Spatiotemporally controlled drug release via a click-release system utilizing mono-alkyl-hydroxylamine and cyclooctyne chemistry.

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.