Cascade Thiol-Responsive Hydrogels Based on Poly(2-Isopropenyl-2-oxazoline) Cross-Linked with Ellman’s Reagent as Disulfide-Containing Cross-Linkers

Abstract Thiol compounds play vital roles in environmental and biological systems, contributing to essential physiological processes, and there is a strong demand for methods to detect thiols and to design thiol-responsive materials. While stimuli-responsive hydrogels have been widely explored for biomedical and nonbiomedical applications, thiol-responsive hydrogels for thiol monitoring and detection remain scarcely reported. Herein, we present a straightforward strategy for synthesizing thiol-responsive hydrogels based on poly(2-isopropenyl-2-oxazoline) (PiPOx) bearing reactive 2-oxazoline side groups, cross-linked with Ellman’s reagent containing a disulfide linker. Disulfide bonds are incorporated into the hydrogel network through ester–amide junctions formed between the 2-oxazoline rings of PiPOx and the carboxylic acid groups of Ellman’s reagent. Upon exposure to thiols, the hydrogels undergo disulfide–thiol exchange reactions, releasing thiophenolate moieties and generating red coloration that enables rapid naked-eye colorimetric detection. Unexpectedly, the released thiophenolate groups further react with remaining 2-oxazoline groups of PiPOx, leading to decoloration accompanied by further evolution of the mechanical properties and enhancement of the hydrogel modulus. Consequently, a single thiol exposure induces a time-dependent cascade response involving swelling, softening, and coloration, followed by shrinking, stiffening, and decoloration. The timing of these events depends on thiol concentration, highlighting the potential of these hydrogels for time-programmable sensing and multilevel cascade-responsive materials.