"All-in-One" MnO2@PtAuRu Nanoreactor for Self-Replenishing and Cascade Catalytic Therapy of Cancer.

Limited by the insufficient catalytic substrates such as H2O2 and O2 in the tumor microenvironment (TME), the continual propelling of nanozymes catalysis therapy of cancer remains a challenge. Here, an all-in-one MnO2@PtAuRu nanoreactor is constructed for self-propelled and cascade catalytic therapy of tumors. The MnO2@PtAuRu is constructed by using hollow MnO2 (≈150 nm) as the core-carrier and ultrasmall PtAuRu nanoclusters (≈2 nm) anchoring on the surface MnO2. According to the glucose oxidase (GOD)/catalase (CAT)/peroxidase (POD) mimic multienzyme activity of PtAuRu nanoclusters, cascaded nanocatalytic reactions can be self-replenishing to persistently produce •OH for superior chemodynamic therapy (CDT). Additionally, the MnO2 carrier can protect the ultrasmall PtAuRu nanoclusters during the circulation and the overexpressed glutathione (GSH) in the tumor can also be degraded by the MnO2 to synergy the CDT. The MnO2@PtAuRu displays obvious photothermal properties which further enhance the cascade catalytic ability and synergistic therapeutic effect. Therefore, this all-in-one nanozyme provides a promising strategy for the rational design of self-replenishment and self-replenishing cascade catalytic therapy of cancer.

Tumor Targeted Cuprous-Based Nanocomposite as Responsive Cascade Nanocatalyst for Efficient Tumor Synergistic Therapy.

The single-functionality of traditional chemodynamic therapy (CDT) reagents usually limits the therapeutic efficacy of cancer treatment. Synergistic nanocomposites that involve cascade reaction provide a promising strategy to achieve satisfactory anticancer effects. Herein, a cuprous-based nanocomposite (CCS@GOx@HA) is fabricated, which owns the tumor targeting ability and can undergo tumor microenvironment responsive cascade reaction to enhance the tumor therapeutic efficiency significantly. Surface modification of nanocomposite with hyaluronic acid enables the targeted delivery of the nanocomposite to cancer cells. Acid-triggered decomposition of nanocomposite in cancer cell results in the release of Cu+ , Se2- and GOx. The Cu+ improves the Fenton-like reaction with endogenous H2 O2 to generate highly toxic • OH for CDT. While GOx can not only catalyze the in situ generation of endogenous H2 O2 , but also accelerate the consumption of intratumoral glucose to reduce nutrient supply in tumor site. In addition, Se2- further improves the therapeutic effects of CDT by upregulating the reactive oxygen species (ROS) in tumor cells. Meanwhile, the surface modification endows the nanocomposite the good water dispersibility and biocompatibility. Moreover, in vitro and in vivo experiments demonstrate satisfactory anti-cancer therapeutic performance by the synergistic cascade function of CCS@GOx@HA than CDT alone.

"Four-in-One" Nanozyme and Natural Enzyme Symbiotic System of Cu2-x Se-GOx for Cervical Cancer Therapy.

Cervical cancer, as a common malignant tumor of the reproductive system, seriously threatens women's life and health, and is difficult to be cured by traditional treatments, such as surgery, chemotherapy and radiotherapy. Fortunately, tumor microenvironment (TME)-activated catalytic therapy with high efficiency and reduced off-target toxicity has emerged as a novel treatment model. Herein, we designed a "four-in-one" nanozyme and natural enzyme symbiotic system of Cu2-x Se-GOx for TME-triggered cascaded catalytic enhanced cancer treatment. In response to unique TME, Cu2-x Se with catalase activity could effectively catalyze over-expressed H2 O2 in cancer cells into O2 . Subsequently, the glucose oxidase (GOx) could deplete intracellular glucose with the assistance of O2 ; this not only achieves starvation therapy, but also regenerates H2 O2 to boost the generation of highly cytotoxic . OH due to the peroxidase activity of Cu2-x Se. Moreover, although the free-radical scavenger glutathione (GSH) is overexpressed in tumor cells, Cu2-x Se with glutathione oxidase activity could effectively consume GSH for enhanced ROS production. Thus, the "four-in-one" nanozyme@natural enzyme symbiotic system of Cu2-x Se-GOx could induce significant ROS accumulation at the tumor regions, thus providing a potential approach for the treatment of cervical cancer.

Biocatalytic Depletion of Tumorigenic Energy Sources Driven by Cascade Reactions for Efficient Antitumor Therapy.

Glucose and lactate play important roles for tumor growth. How to simultaneously deprive tumors of glucose and lactate is a big challenge. We have developed a cascade catalytic system (denoted as FPGLC) based on fluorinated polymer (FP) with co-loading of glucose oxidase (GOx), lactate oxidase (LOx), and catalase (CAT). GOx and LOx deprive glucose and lactate, respectively, resulting in abundant hydrogen peroxide (H2 O2 ) generation. Meanwhile, CAT catalyzes H2 O2 into O2 , which not only promotes catalytic reactions of GOx and LOx for consuming more glucose and lactate, but also alleviates tumor hypoxia. Benefiting from the excellent cross-membrane and transmucosal penetration capacities of FP, FPGLC rapidly accumulated in tumors and subsequently mediated enhanced cascade catalytic therapy under the guidance of photoacoustic imaging. These results demonstrate that the dual depletion of glucose and lactate with O2 supply is a promising strategy for efficient antitumor starvation therapy.

"Three-in-One" Nanozyme Composite for Augmented Cascade Catalytic Tumor Therapy.

Cascade catalytic reaction exhibits simple procedure and high efficiency, such as that from the orderly assembly of different enzymes in biological systems. Mimicking of the natural cascade procedure becomes critical, but the orderly assembly of different enzymes is still challenging. Herein, single Au-Pt nanozyme is reported with "three-in-one" functions to initiate cascade conversions for O2 supply as mimic catalase, H2 O2 production with its glucose oxidase-like property, and • OH generation as mimic peroxidase for chemodynamic therapy (CDT). Thus, the complex assembly and cross-talk among the different enzymes are avoided. To this end, metastable Cu2 O NPs, as scaffolds, are used to anchor ultrasmall Au-Pt nanozyme, while metal-organic framework (MOF) is used to encapsulate the nanozyme for tumor microenvironment response and shielding protein adsorption. Pluronic F127 is then modified on the surface to improve hydrophilicity and biocompatibility of the composite. The endogenous acidity and glutathione in tumor degrade MOF to expose nanozyme for cascade catalytic CDT. The high photothermal conversion ability also enhances the CDT, while Cu2+ ions consume GSH to further improve CDT efficiency as augmented cascade catalytic tumor therapy. Thus, a new paradigm is provided with drug-free single nanozyme for improving tumor therapeutic efficacy and minimizing side effects.

Catalytically Active Metal-Organic Frameworks Elicit Robust Immune Response to Combination Chemodynamic and Checkpoint Blockade Immunotherapy.

Chemodynamic therapy (CDT) strategies rely on the generation of reactive oxygen species (ROS) to kill tumor cells, with hydroxyl radicals (•OH) serving as the key mediators of cytotoxicity in this setting. However, the efficacy of CDT approaches is often hampered by the properties of the tumor microenvironment (TME) and associated limitations to the Fenton reaction that constrains ROS generation. As such, there is a pressing need for the design of new nanoplatforms capable of improving CDT outcomes. In this study, an Fc-based metal-organic framework (MOF) vitamin k3 (Vk3)-loaded cascade catalytic nanoplatform (Vk3@Co-Fc) was developed. This platform was capable of undergoing TME-responsive degradation without impacting normal cells. After its release, Vk3 was processed by nicotinamide adenine dinucleotide hydrogen phosphate (NAD(P)H) quinone oxidoreductase-1 (NQO1), which is highly expressed in tumor cells, thereby yielding large quantities of H2O2 that in turn interact with Fe ions via the Fenton reaction to facilitate in situ cytotoxic •OH production. This process leads to immunogenic cell death (ICD) of the tumor, which then promotes dendritic cell maturation and ultimately increases T cell infiltration into the tumor site. When this nanoplatform was combined with programmed death 1 (PD-1) checkpoint blockade approaches, it was sufficient to enhance tumor-associated immune responses in breast cancer as evidenced by increases in the frequencies of CD45+ leukocytes and CD8+ cytotoxic T lymphocytes, thereby inhibiting tumor metastasis to the lungs and improving murine survival outcomes. Together, this Vk3@Co-Fc cascading catalytic nanoplatform enables potent cancer immunotherapy for breast cancer regression and metastasis prevention.