Supramolecular PEG-DNA-Ferrocene Nanogels for Synergistically Amplified Chemodynamic Therapy via Cascade Reactions

Chemodynamic therapy (CDT) has been limited by the tumor microenvironment, such as the low concentration of hydrogen peroxide (H₂O₂). The combination of therapeutic strategies that increase H₂O₂ with CDT can synergistically enhance the therapeutic effect. Herein, a novel supramolecular PEG-DNA-ferrocene nanogel that can codeliver glucose oxidase (GOx) and the hypoxia-activable prodrug tirapazamine (TPZ) was developed to synergistically amplify CDT via cascade reactions. The DNA nanogel was size-controllable and DNase I-responsive and exhibited good biocompatibility. Induced by oxygen consumption and H₂O₂ generation in the catalytic reaction of GOx, the drugs TPZ and ferrocene in the nanogel underwent the hypoxia-based reaction and the Fenton reaction, respectively. The vitro model tests, intracellular ROS test, MTT experiments, and DNA damage assay demonstrated that the H₂O₂-based cascade Fenton reaction and the hypoxia-based cascade reaction obviously increased ·OH generation and promoted the apoptosis of cancer cells. This cascade supramolecular nanoplatform provided a promising therapeutic strategy to synergistically amplify CDT.