Iron-glucose oxidase nanogel assembly for amplified starvation-ferroptosis anti-tumor therapy

Developing advanced and effective enzyme-drug systems for cancer treatment is of significant interest. Herein, a novel approach is reported to create a highly active and robust enzyme-drug system. Glucose oxidase nanogels (nGOx) are first synthesized by polymerization on the surface of GOx using vinylimidazole as comonomers. Fe³⁺ are utilized to induce self-assembly of nGOx through the imidazole-metal coordination interaction to form GOx nanogel clusters (Fe@nGOx), enhancing the permeability and retention of nGOx into tumor cells by EPR effect. nGOx can deplete glucose in the presence of oxygen and generate H₂O₂, which is converted to highly cytotoxic hydroxyl radical (·OH) by Fe³⁺ and GSH, and the proximity between Fe³⁺ and GOx act in tandem for enhanced tumor therapy. The Fe^III/Fe^II redox cycle reacts with GSH and H₂O₂, enabling continuous generation of ·OH within tumor cells, thus facilitating the anticancer effect. Moreover, the generation of H₂O₂ and ·OH can further promote the repolarization of tumor-associated macrophages from an M2 phenotype towards an M1 phenotype polarization, thus enhancing immune response. The cascade reaction between GOx and Fe³⁺/Fe²⁺ endows Fe@nGOx with excellent anti-tumor efficacy in mice models, highlighting its potential as a promising anticancer drug for clinical applications. This work establishes a new platform for utilizing enzyme/protein and metal ion complexes in versatile applications, advancing the field of enzyme-based cancer therapies.