H₂O₂‐Responsive Nanogel for Enhancing Chemodynamic Therapy

Abstract As a typical chemodynamic therapy (CDT), the Fenton reaction holds great promise in cancer therapy for its effective generation of the cytotoxic hydroxyl radical (^.OH) in situ which induces cancer cell apoptosis. However, the tumor microenvironment is insufficient to meet the optimal conditions for Fenton reaction, which greatly reduces the rate of Fenton reaction and the therapeutic effect of CDT, thereby hindering its application in cancer therapy. Herein, a novel biocompatible nanogel comprised of ferroferric oxide modified β‐cyclodextrin (Fe₃O₄@β‐CD), glucose oxidase (GO_X), and ferrocene (Fc) was fabricated using the host‐guest self‐assembly method for synergistic tumor therapy (Fe₃O₄−GO_X nanogel, FGgel). In the tumor microenvironment, the intratumoral hydrogen peroxide (H₂O₂) could oxidize Fc, leading to the disintegration of the FGgel and the release of GO_X. Subsequently, the released GO_X could catalyze glucose to produce gluconic acid and promote the production of H₂O₂. Meanwhile, in acidic conditions, F₃O₄ served as the Fenton reagent to convert excessive H₂O₂ into highly toxic ^.OH which finally induces tumor cell apoptosis. Extensive in vitro and in vivo studies have confirmed that FGgel can effectively inhibit tumor cell growth with high tumor specificity and good biocompatibility. The excellent anticancer efficiency of FGgel indicates that it is an ideal H₂O₂‐activated nanosystem. As an excellent platform to harness the highly toxic reactive oxygen species in nanomedicine for specific cancer therapy, this strategy may open new doors for further development of progressive therapeutic systems.