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.

The enhanced permeability and retention (EPR) effect alone is not enough for nanoparticles to reach the target. Combination of active and passive targeting may be an effective drug delivery route. Hollow ferric-tannic acid complex nanocapsules (HFe-TA) may effectively degrade and release Fe²⁺ ions, and Fe²⁺ ions induce the production of ·OH, however, the fenton reaction needs amount of H₂O₂ to enhance chemodynamic therapy. Due to their deficiencies, such nanoparticles cannot realize intravenous drug delivery. Here, the mesothelin-targeted membrane (MTM) was constructed to realize accurate delivery nano-system, and mesothelin antibody was expressed on the 293T cell membrane to prepare a MTM. Lactate oxidase (Lox) was loaded on HFe-TA to obtain Lox@HFe-TA. Lox@HFe-TA was coated with MTM to develop the MTM nanosystem. Tirapazamine (TPZ) therapy also requires hypoxia circumstance. The MTM nanosystem combined with TPZ can significantly kill tumour cells and inhibit metastasis in vivo and in vitro. We also tested the biological safety of the treatment. In this study, we overcame the EPR defects via the MTM nanosystem, which can realize acute targeted delivery to the tumour site, lactate depletion, promoted reactive oxygen species (ROS) induction, and enhanced the effect of TPZ, demonstrating a potential synergistic combination of cancer therapy with better efficacy and biosafety.

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.

Multidrug resistance (MDR) restricts chemotherapy efficacy due to P-glycoprotein (P-gp) mediated drug efflux, whereas current approaches to suppressing P-gp expression suffer from intrinsic challenges, such as low transfection, high toxicity and poor specificity. Here, hollow ferric-tannic acid complex nanocapsules (HFe-TA), which can be effectively degraded by the reaction with adenosine triphosphate (ATP), are synthesized for the delivery of glucose oxidase (GOx) and doxorubicin (DOX) for tumor treatment. The findings indicate that the intracellular ATP is significantly decreased due to the combined effect of HFe-TA degradation and GOx-mediated glucose consumption. Along with this ATP down-regulation, P-gp expression of tumor cells is suppressed remarkably, which in turn promotes the intracellular accumulation and anticancer efficacy of DOX. In addition, the production of •OH by Fe ions released from HFe-TA is promoted by the by-products of the oxidation of glucose process by GOx. In consequence, HFe-TA nanocapsules loaded with DOX and GOx enable significant inhibition effect to tumors both in vitro and in vivo due to the synergistic effect of cascade reactions. This study has therefore provided an alternative therapeutic platform for effective tumor inhibition with the potential in overcoming intrinsic MDR.

Electrodynamic therapy (EDT) is a conceptually new cancer treatment approach recently proposed by our group. During EDT, the electro-driven catalytic reaction would occur on the surface of platinum nanoparticles (PtNPs) to produce reactive oxygen species (ROS) under the direct current (DC) or square-wave alternating current (AC) electric field. To further extend the potential of EDT, we hereby designed mesoporous silica-based nanocomposites decorated with PtNPs and loaded with anticancer drug doxorubicin (DOX) for synergistic electrodynamic-chemotherapy. Such silica-based nanocomposites could enable homogenous killing of large-sized tumors (over 500 mm³) and realize remarkable tumor destruction efficacy at a relatively low quantity of electricity. To our best knowledge, this is the first study to combine EDT and chemotherapy to develop a synergetic nanoplatform, openning a new dimension for the design of other EDT-based anticancer strategies.