A tumor-targeted MOF nanoplatform for synergistic ferroptosis-chemotherapy <i>via</i> cascade-activated enzyme–chlormethine prodrug

H₂O₂-activated prodrugs have been developed to alleviate the severe side effects of chemotherapy. However, achieving precise and efficient delivery, along with high activation and release efficiency at the target site, remains a significant challenge. In this study, we combined a H₂O₂-generating enzyme (glucose oxidase, GOx) with a H₂O₂-sensitive chlormethine prodrug <i>via</i> ''reversible click'' chemistry between amino groups of the enzyme and phenyl boronic acid groups of the prodrug. The resulting enzyme-prodrug complex (G-P) was encapsulated in a glutathione (GSH)-responsive iron-based metal organic framework decorated with hyaluronic acid (HA) for tumor-targeted, synergistic ferroptosis-chemotherapy. With the assistance of HA, the resulting nanoparticles (G-P@MOF@HA) demonstrated selective intracellular delivery to CD44-overexpressed tumor cells. Once internalized, the nanoparticles disassembled in the presence of GSH, releasing the G-P complex. GOx catalyzed the conversion of glucose, leading to the generation of sufficient H₂O₂, enabling <i>in situ</i> activation of the prodrug to elicit chemotherapy. Simultaneously, the Fenton reaction between H₂O₂ and Fe²⁺ produced cytotoxic hydroxyl radicals, amplifying ferroptosis. As a consequence, the synergistic therapy group showed superiority over monotherapy in both <i>in vitro</i> and <i>in vivo</i> anticancer studies. This work provides a more efficient and precise strategy for future cancer therapies.