Engineering functional nanomaterials with high therapeutic efficacy and minimum side effects has increasingly become a promising strategy for cancer treatment. Herein, a reactive oxygen species (ROS) enhanced combination chemotherapy platform is designed via a biocompatible metal-polyphenol networks self-assembly process by encapsulating doxorubicin (DOX) and platinum prodrugs in nanoparticles. Both DOX and platinum drugs can activate nicotinamide adenine dinucleotide phosphate oxidases, generating superoxide radicals (O ). The superoxide dismutase-like activity of polyphenols can catalyze HO generation from O . Finally, the highly toxic HO free radicals are generated by a Fenton reaction. The ROS HO can synergize the chemotherapy by a cascade of bioreactions. Positron emission tomography imaging of Zr-labeled as-prepared DOX@Pt prodrug Fe nanoparticles (DPPF NPs) shows prolonged blood circulation and high tumor accumulation. Furthermore, the DPPF NPs can effectively inhibit tumor growth and reduce the side effects of anticancer drugs. This study establishes a novel ROS promoted synergistic nanomedicine platform for cancer therapy.