Hierarchical Bond Programming Enables Triphasic Chemotherapy from an Injectable Tumor-Responsive Hydrogel

Abstract Localized chemotherapy requires sustained yet dynamically regulated drug exposure to match the evolving therapeutic demands within solid tumors. However, existing hydrogel depots are predominantly governed by passive diffusion or single-trigger activation, limiting their ability to achieve spatiotemporally programmed drug release. Here, we report a hierarchically programmed injectable hydrogel platform that enables triphasic chemotherapy through orthogonal bond dissociation pathways. The system integrates physically encapsulated 6-mercaptopurine (6 MP) together with two polymeric prodrugs containing redox-responsive and hydrolytically labile linkages, thereby establishing sequential release processes governed by diffusion, glutathione-triggered cleavage, and bond hydrolysis. This multilevel release architecture enables immediate therapeutic intervention, tumor-microenvironment-activated intracellular drug liberation, and sustained intratumoral maintenance. The hydrogel exhibits excellent injectability, prolonged local retention, and sustained release behavior under tumor-associated conditions (>90% over 200 h). In colorectal tumor models, the hierarchically programmed system significantly enhanced intratumoral drug exposure, achieved 71% tumor inhibition, and reduced systemic toxicity compared with free-drug administration. By coupling orthogonal chemical activation with localized hydrogel delivery, this work establishes a generalizable strategy for spatiotemporally regulated chemotherapy through hierarchical bond programming.