Multi-Enzyme Cascade-Triggered Nitric Oxide Release Nanoplatform Combined with Chemo Starvation-like Therapy for Multidrug-Resistant Cancers

Tumor drug resistance has long been a major challenge in medical oncology. Ferroptosis is a form of regulated cell death with promising clinical applications. However, the efficacy of ferroptosis-inducing agents is often limited by endogenous factors when used alone, and thus, synergistic therapy offers a promising strategy to address this issue. In this study, we developed an iron-doped metal–organic framework (MOF), Fe/ZIF-8, loaded with glucose oxidase (Gox), l-arginine (l-arg), and adriamycin hydrochloride (Dox). The folic acid (FA)-targeted ZIF-8 (GLDFe/Z-FA) prepared was shown to be a multifunctional nanoparticle based on endogenous hydrogen peroxide (H2O2) and glucose, which trigger adaptive cellular responses in cancer cells. The intracellular glucose level and adenosine-triphosphate (ATP) content decreased, indicating that GLDFe/Z-FA reduced the glucose metabolic rate and induced tumor starvation. And the generated •OH and H2O2 induced reactive oxygen species (ROS) overload to implement chemodynamic therapy (CDT). ROS catalyzed l-arg released from GLDFe/Z-FA to release nitric oxide (NO), which inhibited P-glycoprotein expression, prevented Dox efflux, and accumulated intracellular content of Dox to enhance cytotoxicity. GLDFe/Z-FA also catalyzed glutathione degradation, which further disrupted intracellular redox homeostasis, enhanced CDT, and induced cell death. It was shown to follow the ferroptosis pathway and strongly inhibited tumor proliferation both in vitro and in vivo. These findings demonstrate that GLDFe/Z-FA effectively inhibits tumor proliferation, highlighting its potential as a viable therapeutic approach to suppress cancer progression.