Acidogenesis‐Propelled Coordination Transition in Light‐Triggered Fe‐Polyphenol Polymer for Reactive Oxygen Species‐Augmented Antitumor Therapy

Abstract Iron‐based Fenton agents have emerged as promising candidates for tumor therapy due to its excellent selectivity, yet their therapeutic potential is substantially constrained by inefficient Fe ³⁺ /Fe ²⁺ conversion in the tumor microenvironment. Herein, based on a coordination engineering strategy, a light‐responsive Fe‐polyphenol coordination polymer (FeBPs), integrating Fe centers, Bodipy‐based photoacid generators, and PEG‐stabilized polyphenol ligands, is designed to explore how to accelerate the transformation efficiency of Fe ³⁺ to Fe ²⁺ by incorporating both internal and external factors. In terms of internal factors, upon irradiation at 630 nm, the FeBPs trigger the exposure of catalytic sites derived from the coordination transition nature of iron and polyphenol, induced by light‐triggered acidification. Additionally, the Fe ²⁺ regeneration efficiency is also enhanced by changes in the external environment, such as a decrease in pH. Both the light triggered internal and external factors can amplify reactive oxygen species (ROS) fluxes, which disrupt mitochondrial function and induce cell apoptosis, achieving tumor‐specific homeostasis perturbation. In melanoma‐bearing mouse models, FeBPs exhibit complete tumor regression. The findings establish a paradigm for iron‐based therapeutics by harnessing acid‐triggered metal‐ligand cooperativity, overcoming critical limitations of pH dependency and inefficient Fe ³⁺ /Fe ²⁺ conversion, and will provide a foundational framework for adaptive metallopolymeric theranostics.