Glutathione-Responsive Biodegradable Core–Shell Nanoparticles That Self-Generate H₂O₂ and Deliver Doxorubicin for Chemo–Chemodynamic Therapy

As a kind of reactive oxygen species (ROS)-mediated cancer therapy modality, chemodynamic therapy (CDT) has been extensively explored. However, the insufficient endogenous H2O2 and the intracellular redox homeostasis greatly obstruct the anticancer efficacy. Developing multifunctional nanomedicine which can address these issues is appealing. Herein, 4T1 cancer cell membrane (CM)-coated glutathione (GSH)-responsive biodegradable biomimetic nanoreactor, CaO2@MnO2–DOX@CM, was fabricated for tumor oxidative stress amplification enhanced self-supplying H2O2 chemodynamic therapy and synergistic chemotherapy. Highly expressed GSH in the tumor cells could trigger the biodegradation of CaO2@MnO2–DOX@CM, and the Fenton-like catalyst Mn2+ and chemotherapy drug doxorubicin (DOX) were released. The unprotected CaO2 further reacted with water to generate a large amount of H2O2 and Ca2+. The self-supplying H2O2 not only reacted with Mn2+ to generate hydroxyl radical (•OH) but also sped up the biodegradation of the nanoreactor. Furthermore, the MnO2-mediated GSH depletion and the Ca2+-overloading-induced mitochondria dysfunction could further enhance the CDT efficiency. Thus, the glutathione-responsive biodegradable core–shell nanoparticles achieved MRI-guided synergistic chemo–chemodynamic therapy, showing bright prospect for highly efficient tumor treatment.