Surface engineered iron oxide nanozyme for synergistic chemodynamic/photodynamic therapy with glutathione depletion and hypoxia relief

Reactive oxygen species (ROS)-based therapies, such as photodynamic therapy (PDT) and chemodynamic therapy (CDT), hold great promise to cancer treatment. However, their efficacies are subject to hypoxia and overexpressed glutathione (GSH) in tumor microenvironment (TME). Herein, we develop Mn (II) ions and pyropheophorbide (PPa) engineered iron oxide nanoparticles (IMOP) to regulate tumor hypoxia and deplete GSH for synergistic CDT/PDT. In the TME, IMOP could catalytically decompose hydrogen peroxide (H2O2) to hydroxyl radicals (·OH) as a CDT agent. Significantly, IMOP exhibits high catalase-like and glutathione peroxidase-like activities simultaneously. Once enriching into tumor, IMOP could catalyze H2O2 to oxygen (O2) to overcome hypoxic TME for improved 1O2 generation via PPa-mediated PDT. Meanwhile, the glutathione peroxidase-like activity ensure IMO to reduce the intratumoral GSH concentration and further reduce the consumption of active ROS during therapy. We demonstrated that the regulation by IMOP elicited synergistic CDT/PDT efficacy for enhanced ROS-based cancer treatment both in vitro and in vivo. Moreover, the existence of Mn (II) allowed IMO with T1 contrast behavior to monitor the progress of CDT/PDT in magnetic resonance imaging. This work provides a new guidance for designing TME-based anticancer platform for effective and precise cancer treatment.