A mitochondria-targeted PFAGD nanogel mitigates tumor hypoxia and enables sustained, localized ROS generation, offering a promising strategy for catalytic anticancer therapy.
Abstract
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.
BIMLM is developed as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication.
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The hypoxic and immunosuppressive tumor microenvironment limits photodynamic therapy (PDT). We designed a TME-responsive nanoplatform (Ir@MnO2@TK/FA) with MnO2 nanoshells, a perfluorocarbon (PFC)-modified iridium(III) photosensitizer (Ir-PFC), a reactive oxygen species (ROS)-responsive polymer, and a tumor-targeting folic acid ligand. MnO2 decomposes H2O2 to O2, and PFC stores O2, together alleviating hypoxia. Upon light irradiation, enhanced O2 boosts ROS generation via type I/II pathways. In vitro and in vivo studies show efficient O2 self-supply, multiple ROS production, potent cytotoxicity under hypoxia, and induction of necroptosis, pyroptosis, and immunogenic cell death. Released Mn2+ activates cGAS-STING. In vivo, the system relieves hypoxia and reverses immunosuppression. Overall, this work introduces an innovative nanoplatform that establishes a self-reinforcing cycle of hypoxia alleviation and immune activation, offering a potent combinatorial strategy to surmount PDT resistance and amplify antitumor immunity.
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