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). Cu 2 O can effectively release Cu + within the TME, facilitating CDT, and concurrently generate O 2 to mitigate hypoxia. Co-delivery of Cu 2 O 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 Cu 2 O. To overcome these limitations, we propose the utilization of Cu 2 O as the core within GSH-responsive metal–organic framework (MOF) shells, uniformly grown on its surface to form Cu 2 O@MOFs heterostructures. This design effectively prevents leakage and deactivation of the Cu 2 O core. We synthesized Cu 2+ -doped ZIF-67 multifunctional MOF shells in situ on Cu 2 O and subsequently incorporated the photosensitizer ZnPc into the MOFs to create Cu 2 O@Cu 2+ /ZIF-67@ZnPc (CCZZ). Upon entry into tumor cells, this nanodrug degrades in the presence of slight acidity and an optimal GSH concentration, releasing Cu 2 O and ZnPc while depleting GSH. The released Cu 2 O and degraded ZIF-67, respectively, generate Cu + and Co 2+ for CDT and O 2, while the ZnPc consumes O 2 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 Cu 2 O@Cu-MOFs that achieves dual-enhanced PDT/CDT therapy by simultaneously depleting GSH and generating oxygen.