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Graphical abstract, Introduction Hypoxic tumor microenvironment (TME) is the major contributor to cancer metastasis, resistance to chemotherapy, and recurrence of tumors. So far, no approved treatment has been available to overcome tumor hypoxia. Objectives The present study aimed to relieve tumor hypoxia via a nanozyme theranostic nanomaterial as well as providing magnetic resonance imaging (MRI)-guided therapy. Methods Manganese dioxide (MnO2) was used for its intrinsic enzymatic activity co-loaded with the anti-cancer drug Doxorubicin (Dox) within the recombinant heavy-chain apoferritin cavity to form MnO2-Dox@HFn. Following the synthesis of the nanomaterial, different characterizations were performed as well as its nanozyme-like ability. This nanoplatform recognizes tumor cells through the transferrin receptors 1 (TfR1) which are highly expressed on the surface of most cancer cells. The cellular uptake was confirmed by flow cytometry and fluorescence spectroscopy. In vitro and in vivo studies have been investigated to evaluate the hypoxia regulation, MRI ability and anti-tumor activity of MnO2-Dox@HFn. Results Being a TME-responsive nanomaterial, MnO2-Dox@HFn exerted both peroxidase and catalase activity that mainly produce massive oxygen and Mn2+ ions. Respectively, these products relieve the unfavorable tumor hypoxia and also exhibit T1-weighted MRI with a high longitudinal relaxivity of 33.40 mM. s−1. The utility of MnO2-Dox@HFn was broadened with their efficient anti-cancer activity proved both in vitro and in vivo. Conclusions MnO2-Dox@HFn successfully overcome tumor hypoxia with double potentials enzymatic ability and diagnostic capacity. This investigation could ignite the future application for cancer theranostic nanozyme therapy.