Tumor-targeted nanoplatform for synergistic ferroptosis-chemotherapy via in situ cascade-activated enzyme-chlormethine prodrug and metal organic frameworks
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 via ‘‘reversible click’’ chemistry between amino groups on enzyme and phenyl boronic acid groups on 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 into sufficient H2O2, enabling in situ activation of prodrugs 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 in vitro and in vivo anticancer studies. This work provides a more efficient and precise strategy for future cancer therapies.
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