Cascade-Enhanced Chemodynamic Therapy via a Mitochondria-Targeted PEI-Fc-Gox Nanogel with Dual Antihypoxia and ROS Amplification.

The glucose oxidase (GOx)-catalyzed oxidation of glucose generates an acidic microenvironment and supplies H2O2 as the essential substrate for intracellular Fenton reactions. However, the efficiency of this process is often constrained by the hypoxic conditions in tumor tissues. To address this limitation, we developed a mitochondria-targeted PFAGD nanogel, by covalently conjugating ferrocene (Fc) and GOx onto a polyethylenimine (PEI) backbone and encapsulating atovaquone (ATO), a mitochondrial respiration inhibitor. Surface modification with DNA-TPP enabled mitochondrial targeting. The incorporated ATO effectively alleviated intracellular hypoxia, thereby promoting the GOx/Fc-mediated cascaded Fenton reaction. This process drove substantial ROS (particularly ·OH) generation, thereby amplifying chemodynamic therapy. Multiple cellular assays confirmed that the three-step cascade reaction in the PFAGD nanogel enhanced the proliferation inhibition effect on cancer cells, especially under hypoxic conditions. This self-reinforcing nanoplatform mitigates tumor hypoxia and enables sustained, localized ROS generation, offering a promising strategy for catalytic anticancer therapy.