A multimodal strategy of Fe3O4@ZIF-8/GOx@MnO2 hybrid nanozyme via TME modulation for tumor therapy

Abstract

Weak acidity (6.5–6.9) and limited H₂O₂ level in the tumor microenvironment (TME) usually impact the therapeutic effect of chemodynamic therapy (CDT) for cancer. A Specific TME promotes the formation of an immunosuppressive microenvironment and results in high rate of recurrence and metastasis of cancer. Fe₃O₄@ZIF-8/GOx@MnO₂ multi-layer core shell nanostructure was constructed as a hybrid nanozyme. After magnetic targeting of the tumor site, the outermost MnO₂ shell catalyzed H₂O₂ in TME to produce O₂ and was broken due to the reaction with glutathione. Due to the acid response, the ZIF-8 layer would crack and release glucose oxidase (GOx) and Fe₃O₄. The generated O₂ was utilized by GOx in starvation therapy to consume glucose and produce H₂O₂ and gluconic acid. The Fenton reaction efficiency of Fe(II) was improved by the increased H₂O₂ concentration and the enhanced acidity in TME. At the same time, the intrinsic photothermal effect of Fe₃O₄ upon 808 nm laser irradiation promoted the activity of MnO₂ and GOx as oxidase, and Fe(II) as catalase-like, and ablated the primary tumor. Moreover, the hybrid nanozyme can facilitate the transformation of M2-type macrophages to M1-type, and strong systemic antitumor immune effect was induced. A synergy of multiple therapeutic modes including starvation therapy, CDT, photothermal therapy (PTT), and immunotherapy can be realized in the hybrid nanozyme for tumor therapy.