Hypoxia is a hallmark of the tumor microenvironment (TME) that promotes tumor development and metastasis. Photodynamic therapy (PDT) is a promising strategy in the treatment of tumors, but it is limited by the lack of oxygen in TME. In this work, an O self-supply PDT system is constructed by co-encapsulation of chlorin e6 (Ce6) and a MnO core in an engineered ferritin (Ftn), generating a nanozyme promoted PDT nanoformula (Ce6/Ftn@MnO ) for tumor therapy. Ce6/Ftn@MnO exhibits a uniform small size (15.5 nm) and high stability due to the inherent structure of Ftn. The fluorescence imaging and immunofluorescence analysis demonstrate the pronounced accumulation of Ce6/Ftn@MnO in the tumors of mice, and the treatment significantly decreases the expression of hypoxia-inducible factor (HIF)-1α. The Ce6/Ftn@MnO nanoplatform exerts a more potent anti-tumor efficacy with negligible damage to normal tissues compared to the treatment with free Ce6. Moreover, the weak acidity and the presence of H O in TME significantly enhances the r relativity of Ce6/Ftn@MnO , resulting in a prominent enhancement of MRI imaging in the tumor. This bio-mimic Ftn strategy not only improves the in vivo distribution and retention of Ce6, but also enhances the effectiveness and precision of PDT by TME modulation.