In this work, we sought to use our previously reported chemistry on Morita-Baylis-Hillmann (MHB)-adducts 31-37 to develop a new tertiary amine-prodrug platform with biomarker signaltriggered drug activation for controlled delivery (Figure ). This system constitutes a straightforward and widely applicable method for the formation of stable quaternary amine prodrug conjugates from various amine-containing therapeutics, without the need for long or cumbersome synthetic routes. By using the embedded azide functionality on the prodrug together with an alkyne-functionalized dextran and a bis-azide crosslinker, we developed prodrug conjugated hydrogel structures to demonstrate its material compatibility. The traceless cleavage of conjugated drugs in the material matrix is realized upon the addition of nucleophilic biomarker signals, leading to controlled drug activation (Figure ). We incorporated anticancer prodrugs in a hydrogel and used this material to inhibit in vitro A549 cancer cell proliferation (2D monolayer) to demonstrate signal-controlled drug release.