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.

Nanocatalysts mediated reactive oxygen species (ROS) based therapy has been exploited as an alternative therapeutic modality of tumor with high specificity and minimal side effects. However, the treatment outcome is limited by the efficiency of local catalytic reaction. Herein, we report a novel type of core–shell hybrid nanoparticles (CaCO₃@MS), consisting of CaCO₃ and MnSiO_x, for synergistic tumor inhibition combining enhanced catalytic effect and calcium overload. In this system, MnSiO_x serves as catalysts with glutathione (GSH) responsive Mn²⁺ ions release functionality. CaCO₃ nanoparticles play three important roles, including carbon dioxide (CO₂) donor, pH modulator, and Ca²⁺ overload agent. It is found that the CaCO₃ nanoparticles can induce CO₂ production and pH increase in acidic tumor environment, both of which promote Mn²⁺ mediated ROS generation. And simultaneous release of Ca²⁺ ions from CaCO₃ triggers calcium overload in tumor, which functions collaboratively with excessive ROS to induce cancer cell apoptosis. The results demonstrate that after treatment with CaCO₃@MS, a remarkable tumor inhibition was achieved both in vitro and in vivo, while no clear toxic effect was observed. This study has therefore provided a feasible effective approach to improve catalytic therapeutic efficacy by an “exogenous CO₂ delivery” strategy for combinational tumor therapy.