Biomimetic Synthesis of Multinuclear Metal‐Oxo Bridges Under Mild Aqueous Conditions for Catalytic Cancer Therapy

Abstract

ABSTRACT In biological systems, enzymes achieve efficient catalysis by precisely assembling multinuclear metal‐oxo bridges, such as Fe─O─Fe motifs, under physiological conditions. However, constructing such structures in synthetic systems, particularly under mild aqueous conditions, remains challenging. Here, we report a self‐assembled helical polymer that creates a protein‐like microenvironment and enables the biomimetic construction of Fe─O─Fe structures in a synthetic polymer system under mild, neutral aqueous conditions. This strategy increases the stability constant of iron coordination by two orders of magnitude and endows the resulting complex with pH‐gated catalytic behavior: the complex remains catalytically inert under neutral conditions but exhibits more than 20‐fold enhanced peroxidase‐like activity in the weakly acidic tumor microenvironment. Moreover, oxo‐bridge formation significantly enhances near‐infrared absorption, enabling a robust photothermal effect. Without any exogenous drug payload, the complex selectively induces ferroptosis and immunogenic cell death in tumor cells, leading to complete tumor eradication in a mouse model. This work establishes a biomimetic strategy for constructing metal‐oxo‐bridged clusters and provides mechanistic insights into the structure‐function relationships of metalloprotein‐inspired materials.