Cu2O-Based Core–Shell Nanostructures with Glutathione Depletion and O2 Generation Properties for Photodynamic/Chemodynamic Tumor Therapy

Hypoxia and high glutathione (GSH) contents in the tumor microenvironment (TME) diminish the efficacy of single-modality photodynamic therapy (PDT) and chemodynamic therapy (CDT). Cu2O can effectively release Cu+ within the TME, facilitating CDT, and concurrently generate O2 to mitigate hypoxia. Co-delivery of Cu2O with photosensitizers (PSs) to tumors could potentially enhance PDT/CDT combination therapy. However, challenges such as instability, susceptibility to in vivo substances affecting catalytic activity, and toxicity to normal tissues limit the utility of Cu2O. To overcome these limitations, we propose the utilization of Cu2O as the core within GSH-responsive metal–organic framework (MOF) shells, uniformly grown on its surface to form Cu2O@MOFs heterostructures. This design effectively prevents leakage and deactivation of the Cu2O core. We synthesized Cu2+-doped ZIF-67 multifunctional MOF shells in situ on Cu2O and subsequently incorporated the photosensitizer ZnPc into the MOFs to create Cu2O@Cu2+/ZIF-67@ZnPc (CCZZ). Upon entry into tumor cells, this nanodrug degrades in the presence of slight acidity and an optimal GSH concentration, releasing Cu2O and ZnPc while depleting GSH. The released Cu2O and degraded ZIF-67, respectively, generate Cu+ and Co2+ for CDT and O2, while the ZnPc consumes O2 for PDT under laser irradiation, achieving synergistic PDT/CDT combination therapy. To the best of our knowledge, this is the first study based on the in situ synthesis of Cu2O@Cu-MOFs that achieves dual-enhanced PDT/CDT therapy by simultaneously depleting GSH and generating oxygen.