A Metal–Polyphenol‐Coordinated Nanomedicine for Synergistic Cascade Cancer Chemotherapy and Chemodynamic Therapy

Abstract The clinical application of chemotherapy is impeded by the unsatisfactory efficacy and severe side effects. Chemodynamic therapy (CDT) has emerged as an efficient strategy for cancer treatment utilizing Fenton chemistry to destroy cancer cells by converting endogenous H 2 O 2 into highly toxic reactive oxygen species. Apart from the chemotherapeutic effect, cisplatin is able to act as an artificial enzyme to produce H 2 O 2 for CDT through cascade reactions, thus remarkably improving the anti‐tumor outcomes. Herein, an organic theranostic nanomedicine (PTCG NPs) is constructed with high loading capability using epigallocatechin‐3‐gallate (EGCG), phenolic platinum(IV) prodrug (Pt‐OH), and polyphenol modified block copolymer (PEG‐ b ‐PPOH) as the building blocks. The high stability of PTCG NPs during circulation stems from their strong metal–polyphenol coordination interactions, and efficient drug release is realized after cellular internalization. The activated cisplatin elevates the intracellular H 2 O 2 level through cascade reactions. This is further utilized to produce highly toxic reactive oxygen species catalyzed by an iron‐based Fenton reaction. In vitro and in vivo investigations demonstrate that the combination of chemotherapy and chemodynamic therapy achieves excellent anticancer efficacy. Meanwhile, systemic toxicity faced by platinum‐based drugs is avoided through this nanoformulation. This work provides a promising strategy to develop advanced nanomedicine for cascade cancer therapy.