Glucose oxidase (GOx)-based starvation therapy has emerged as a promising strategy in tumor therapy. However, the non-specific catalytic activity and premature degradation of GOx during systemic circulation have limited its therapeutic efficacy in tumor regions. In this study, we present the synthesis of ultrasound/glutathione dual-responsive ZIF-8-GOx@copper-polydopamine@liposome-L-arginine (ZGCLL) nanoparticles, designed to concurrently achieve ion interference therapy, starvation therapy, and ultrasound-catalyzed gas therapy. The ZIF-8-GOx nanoparticles are prepared via a co-precipitation method, followed by the encapsulation of a copper-polydopamine (Cu-PDA) shell on the particle surface. Subsequently, liposomes and L-arginine are incorporated to form ZGCLL. The Cu-PDA shell exhibits responsiveness to the elevated level of glutathione in tumor microenvironment, leading to its degradation, mitigating the risk of unintended degradation and 'off-target' effect of GOx in normal tissues. The exposure of ZIF-8 results in zinc overload and activates the catalytic reaction of GOx. The consequent depletion of glucose facilitates starvation therapy, while the generated H₂O₂, in synergy with zinc ions, intensifies oxidative stress. H₂O₂ can produce more potent reactive oxygen species when exposed to ultrasound, which subsequently react with L-arginine to generate higher levels of nitric oxide for gas therapy. Both in vitro and in vivo studies demonstrate that this platform achieves precise and efficient antitumor effects. This research offers an innovative strategy for the development of cascade catalytic reaction systems and targeted therapeutic platforms.

Nanozyme is a new promising approach to cancer therapy for its ability to induce ferroptosis by activating H₂O₂ via a traditional radical pathway and enhance cancer immunotherapy. However, short half-life period of hydroxyl radical (·OH) results in unsatisfied effectiveness. Herein, we synthesized a single-atom iron nanozyme (Fe-SAzyme), which can activate H₂O₂ via a non-radical pathway to generate Fe-based reactive oxygen species (ROS) (O=FeO₃=O) for promoting the ferroptosis of pancreatic cancer cells. This Fe-SAzyme could be specifically phagocytosed by pancreatic cancer cells, increasing ROS levels and inhibiting glutathione (GSH) synthesis, which activates ferroptosis. Tumor magnetic resonance imaging (MRI) showed decreased T2 signal after intravenous injection of RGD@Fe-AC (AC = activated carbon). Moreover, RGD@Fe-AC promoted dendritic cell (DC) maturation, overcame Treg-mediated immunosuppression, activated T cells to trigger adaptive immune responses, and enhanced the efficacy of α-PD-L1 immunotherapy. Our research demonstrated that RGD@Fe-AC provided a straightforward, easily implemented, and selective approach for pancreatic cancer treatment and immunotherapy.