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 challengein medicaloncology. Ferroptosis is a form of regulated cell death with promisingclinical applications. However, the efficacy of ferroptosis-inducingagents is often limited by endogenous factors when used alone, andthus, synergistic therapy offers a promising strategy to address thisissue. In this study, we developed an iron-doped metal-organicframework (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 shownto be a multifunctional nanoparticle based on endogenous hydrogenperoxide (H2O2) and glucose, which trigger adaptivecellular responses in cancer cells. The intracellular glucose leveland adenosine-triphosphate (ATP) content decreased, indicating thatGLDFe/Z-FA reduced the glucose metabolic rate and induced tumor starvation.And the generated (OH)-O-& BULL; and H2O2 induced reactive oxygen species (ROS) overload to implement chemodynamictherapy (CDT). ROS catalyzed l-arg released from GLDFe/Z-FAto release nitric oxide (NO), which inhibited P-glycoprotein expression,prevented Dox efflux, and accumulated intracellular content of Doxto enhance cytotoxicity. GLDFe/Z-FA also catalyzed glutathione degradation,which further disrupted intracellular redox homeostasis, enhancedCDT, and induced cell death. It was shown to follow the ferroptosispathway and strongly inhibited tumor proliferation both invitro and in vivo. These findings demonstratethat GLDFe/Z-FA effectively inhibits tumor proliferation, highlightingits potential as a viable therapeutic approach to suppress cancerprogression.

Automated summary

Drug resistance in tumor treatment has always been a major challenge. Ferroptosis, a regulated form of cell death, shows promising clinical applications. However, the effectiveness of ferroptosis-inducing agents is often limited when used alone, and thus, synergistic therapy becomes a potential strategy to address this issue.