A multimodal strategy of FeO@ZIF-8/GOx@MnO hybrid nanozyme TME modulation for tumor therapy.

Weak acidity (6.5-6.9) and limited HO 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. FeO@ZIF-8/GOx@MnO multi-layer core shell nanostructure was constructed as a hybrid nanozyme. After magnetic targeting of the tumor site, the outermost MnO shell catalyzed HO in TME to produce O 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 FeO. The generated O was utilized by GOx in starvation therapy to consume glucose and produce HO and gluconic acid. The Fenton reaction efficiency of Fe(II) was improved by the increased HO concentration and the enhanced acidity in TME. At the same time, the intrinsic photothermal effect of FeO upon 808 nm laser irradiation promoted the activity of MnO 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.