A Metal-Polyphenol-Based Oxygen Economizer and Fenton Reaction Amplifier for Self-Enhanced Synergistic Photothermal/Chemodynamic/Chemotherapy.

To overcome the limitations of doxorubicin (DOX) chemotherapy, nanomedicines that integrate additional photothermal therapy (PTT) and chemodynamic therapy (CDT) strategies have been highlighted as promising alternatives for the treatment of malignant tumors. However, time-consuming preparation processes, biosafety concerns, and individual therapeutic modalities often limit the practical applications of this strategy. To address these issues, we designed an oxygen economizer that additionally serves as a Fenton reaction amplifier through the simple assembly of epigallocatechin gallate (EGCG), pluronic F-127 (PF127), iron (III) ions, and doxorubicin (DOX) for the enhancement of synergistic PTT/CDT/chemotherapy. The resulting nanoformulation, EFPD, can target mitochondria and inhibit cell respiration to reduce O 2 consumption, thus boosting DOX-mediated H 2 O 2 generation for enhanced CDT and simultaneously improving hypoxia-limited DOX chemotherapy efficacy. Moreover, the coordination between EGCG and Fe 3+ provides EFPD with excellent photothermal conversion efficiencies (η = 34.7%) for PTT and photothermal-accelerated drug release. Experimental results indicate that EFPD-meditated synergistic enhancement of PTT/CDT/chemotherapy can achieve excellent therapeutic outcomes, including enhanced ablation of solid tumors, reduced metastasis and cardiotoxicity, and extended life spans. This article is protected by copyright. All rights reserved.