Degradable Tumor-Responsive Iron-Doped Phosphate-Based Glass Nanozyme for H₂O₂ Self-Supplying Cancer Therapy

Tumor microenvironment (TME)-responsive chemodynamic therapy (CDT) mediated by nanozymes has been extensively studied both experimentally and theoretically, but the low catalytic efficiency due to insufficient H₂O₂ in the TME and the poor biodegradability of the nanozymes are still main challenges for clinical translation of nanozymes. Herein, we designed a H₂O₂ self-supplying nanozyme bearing glucose oxidase (GOX) and polyethyleneimine based on a degradable iron-doped phosphate-based glass (FePBG) nanomimic (FePBG@GOX), which can convert endogenous glucose into toxic hydroxyl radicals. The GOX loaded on the nanozyme can effectively consume glucose in tumor cells to produce a large amount of H₂O₂ to make up for the lack of H₂O₂ in the TME. Thereafter, enormous hydroxyl radicals, based on a Fenton reaction of FePBG without any exogenous H₂O₂, are generated to induce severe apoptosis of tumor cells. The nanozyme exhibits enhanced in vitro cytotoxicity in a high-glucose medium than in a low-glucose medium, illustrating sufficient generation of H₂O₂ by GOX. The excellent in vivo antitumor efficacy is manifested by a high tumor growth inhibition ratio of 94.65% in model mice. Excellent intrinsic biodegradability owing to its phosphate-based glass nature is a remarkable advantage of the prepared FePBG nanozyme over most other reported nanozymes. Big concerns about side effects caused by long-time residence in living organisms are eliminated since it degrades not only in an acid medium but also in a neutral physiological environment. Therefore, this novel strategy of the TME-responsive H₂O₂ self-supplying nanozyme based on an endogenous cascade catalytic reaction opens up an avenue for designing degradable nanozymes in CDT.