Peroxide-Simulating and GSH-Depleting Nanozyme for Enhanced Chemodynamic/Photodynamic Therapy via Induction of Multisource ROS

Abstract

Reactive oxygen species (ROS) generation, using photodynamic therapy (PDT) and chemodynamic therapy (CDT), is a promising strategy for cancer treatment. However, the production of ROS in tumor cells is often limited by hypoxia, insufficient substrates, and high level of ROS scavengers in a tumor microenvironment, which seriously affects the efficacy of ROS-related tumor therapies. Herein, we report a lipid-supported manganese oxide nanozyme, MLP@DHA&Ce6, by decorating a MnO₂ nano-shell on the liposome loaded with dihydroartemisinin (DHA) and photosensitizer Ce6 for generating multisource ROS to enhance cancer therapy. MLP@DHA&Ce6 can be accumulated in tumors and can release active components, Mn²⁺ ions, and O₂. The conjugate generates ROS via nanozyme-catalyzed CDT using DHA as a substrate, PDT through Ce6, and the Fenton reaction catalyzed by Mn²⁺ ions. The production of O₂ from MnO₂ enhanced Ce6-mediated PDT under near-infrared light irradiation. Meanwhile, MLP@DHA&Ce6 showed prominent glutathione depletion, which allowed ROS to retain high activity in tumor cells. In addition, the release of Mn²⁺ ions and DHA in tumor cells induced ferroptosis. This multisource ROS generation and ferroptosis effect of MLP@DHA&Ce6 led to enhanced therapeutic effects in vivo.