Co-Delivery of Glucose Oxidase and Iron-Doped ZIF-8 as a pH-Responsive Ferroptosis and Starvation Agent for Triple-Negative Breast Cancer Therapy

Currently, single-modal tumor therapy has significant limitations, while multi-modal combination therapy can overcome this bottleneck and open up new pathways for enhancing the efficacy of tumor therapy. However, it is still difficult to design a functionalized nanocarrier that can simultaneously mediate multiple therapeutic approaches. To tackle this challenge, we developed a multifunctional nano-codelivery system with glucose oxidase (GOx) loaded inside iron-doped zeolitic imidazolate framework-8 (Fe/ZIF-8), abbreviated as GFZ. This system effectively integrates the synergy and complementarity between ferroptosis therapy and starvation therapy (STT). Herein, GFZ innovatively combines the pH sensitivity of the ZIF-8 skeleton with the EPR effect of nanoparticles to achieve on-demand triggered release, significantly improving the accuracy of tumor targeting. Furthermore, GOx-mediated STT effectively alleviates the insufficiency of endogenous H2O2 during the ferroptosis process, thereby enhancing and synergizing with ferroptosis therapy. Experiments demonstrated both in vitro and in vivo that GFZ activates antitumor cascade reactions, inhibits tumor recurrence and metastasis, and exhibits excellent biocompatibility. Consequently, given its remarkable potential, GFZ is poised to emerge as a new mode of nano-delivery platform.