A Purposefully Designed pH/GSH‐Responsive MnFe‐Based Metal‐Organic Frameworks as Cascade Nanoreactor for Enhanced Chemo‐Chemodynamic‐Starvation Synergistic Therapy

Abstract Metal‐organic frameworks (MOFs) have emerged as promising novel therapeutics for treating malignancies due to their tunable porosity, biocompatibility, and modularity to functionalize with various chemotherapeutics drugs. However, the design and synthesis of dual‐stimuli responsive MOFs for controlled drug release in tumor microenvironments are vitally essential but still challenging. Meanwhile, the catalytic effect of metal ions selection and ratio optimization in MOFs for enhanced chemodynamic therapy (CDT) is relatively unexplored. Herein, a series of MnFe‐based MOFs with pH/glutathione (GSH)‐sensitivity are synthesized and then combined with gold nanoparticles (Au NPs) and cisplatin prodrugs (DSCP) as a cascade nanoreactor (SMnFeCGH) for chemo‐chemodynamic‐starvation synergistic therapy. H + and GSH can specifically activate the optimal SMnFeCGH nanoparticles in cancer cells to release Mn 2+/4+ /Fe 2+/3+ , Au NPs, and DSCP rapidly. The optimal ratio of Mn/Fe shows excellent H 2 O 2 decomposition efficiency for accelerating CDT. Au NPs can cut off the energy supply to cancer cells for starvation therapy and strengthen CDT by providing large amounts of H 2 O 2 . Then H 2 O 2 is catalyzed by Mn 2+ /Fe 2+ to generate highly toxic •OH with the depletion of GSH. Meanwhile, the reduced DSCP accelerates cancer cell regression for chemotherapy. The ultrasensitivity cascade nanoreactor can enhance the anticancer therapeutic effect by combining chemotherapy, CDT, and starvation therapy.