Engineering biohybrid nanozymes with near-infrared II light-enhanced catalysis for remodeling tumor microenvironment by disrupting energy metabolism.

The combination of chemotherapy (CT) and chemodynamic therapy (CDT) via nanoscale drug delivery systems has great potential for tumor therapy. Nevertheless, the low intracellular H2O2 and high reductive glutathione (GSH) levels, as well as the mildly acidic conditions (pH 5.8-6.8) of the tumor microenvironment (TME) still limit their further applications. To tackle these problems, a TME-modulating nanoreactor (denoted as Fe3O4-DOX@PDA-GOx@HA, FDPGH) was developed through a simple and practicable method to achieve multiply enhanced CDT synergized with CT, starvation therapy (ST), and photothermal therapy (PTT). Upon cellular uptake, the hyaluronic acid (HA) and PDA shells rapidly collapsed to release Fe3O4, glucose oxidase (GOx) and doxorubicin (DOX), and the overexpressed GSH could promote the reduction of Fe3+ to Fe2+, resulting in CDT activation. GOx-driven oxidation reaction not only produced H2O2 for enhanced CDT, but also killed tumor cells by initiating ST. In addition, the acid amplification caused by gluconic acid production in turn accelerated the degradation of FDPGH, promoting the Fenton reaction to enhance CDT. Most importantly, the nanoreactor had excellent photothermal performance to achieve PTT and PTT-enhanced CDT with the release of DOX into tumor tissue to achieve enhanced CT. This novel cascade nanoreactor with TME-modulating capability is intended to provide further inspiration for multimodal treatment paradigms.

Despite being more effective than single treatments for cancer, combination therapy poses a challenge in integrating multiple modalities. In this study, we propose a nanoplatform (CuS@GOx@ES) that integrates chemodynamic therapy (CDT), starvation therapy (ST), photothermal therapy (PTT), and copper-induced toxicity for enhanced cancer treatment. CuS nanoparticles, with their large surface area, are ideal for CDT, while glucose oxidase (GOx) depletes tumor glucose for ST and catalyzes H2O2 production for a Fenton-like reaction. The glucose depletion generates gluconic acid, which accelerates CuS degradation and Cu2+ release, enhancing both CDT and copper-induced toxicity. CuS also exhibits excellent photothermal properties and enhances PTT under 808 nm NIR irradiation. The increased temperature further amplifies the effects of CDT and copper-induced toxicity. Additionally, CuS serves as an exogenous source of copper, releasing Cu2+ into the tumor microenvironment (TME), where it binds to the copper ion carrier ES for targeted delivery to tumor cells, inducing copper-induced toxicity and tumor cell death. The CuS@GOx@ES nanoplatform effectively combines CDT, PTT, ST, and copper-induced toxicity, creating a synergistic effect where the treatments enhance each other to achieve superior therapeutic outcomes.

Designing multifunctional nanotherapeutic platforms that integrate multiple therapeutic capabilities with enhanced tumor specificity and low systemic toxicity has emerged as a promising strategy for cancer therapy. Herein, we put forward a simple and clear route to construct multifunctional nanoparticles (NPs) integrating chemodynamic therapy (CDT), starvation therapy (ST), and photothermal therapy (PTT) by using polydopamine as a protective layer to coat Cu2+-doped zinc phosphate loaded with glucose oxidase (designated as Cu-ZnP@GOx/PDA/PEG NPs) for optimizing therapeutic efficacy. The obtained Cu-ZnP@GOx/PDA/PEG NPs utilize porous Cu2+-doped ZnP to provide sufficient space for efficient GOx loading, while the PDA shell coated on the surface acts as a "gatekeeper" to prevent enzyme leakage and provides photothermal conversion capabilities. When Cu-ZnP@GOx/PDA/PEG NPs accumulate at tumor sites, the slightly acidic tumor microenvironment triggers the degradation of Cu-ZnP@GOx/PDA/PEG NPs, thereby releasing loaded GOx and doped Cu2+. The released Cu2+ is reduced to Cu+ by glutathione (GSH), subsequently catalyzing H2O2 decomposition to generate highly cytotoxic hydroxyl radicals (•OH) for effective CDT. The released GOx can cut off glucose metabolism in tumor cells to realize ST, and the substances produced during the process of glucose oxidation can improve the microenvironment for better CDT. Under near-infrared irradiation, the generated heat by the photothermal effect of PDA can not only be applied for PTT but also enhance the catalytic efficiency of Fenton-like reactions and the enzymatic activity of GOx, achieving the goal of trimodal synergistic therapy of CDT/ST/PTT. Importantly, in vivo studies using tumor-bearing mice demonstrate that the combined therapy via Cu-ZnP@GOx/PDA/PEG NPs effectively suppresses tumor growth, and no obvious systemic toxicity can be observed. Taken together, the construction of Cu-ZnP@GOx/PDA/PEG NPs can provide a feasible strategy for a safe and efficient cancer therapy.

A multifunctional cascade bioreactor based on a layered double oxides composite hydrogel for synergetic tumor chemodynamic/starvation/photothermal therapy

Chemodynamic therapy (CDT) is an emerging tumor treatment; however, it is hindered by insufficient endogenous hydrogen peroxide (H2O2) and high glutathione (GSH) concentrations in the tumor microenvironment (TME). Furthermore, CDT has limited therapeutic efficacy as a monotherapy. To overcome these limitations, in this study, a nanoplatform is designed and constructed from Cu-doped mesoporous Prussian blue (CMPB)-encapsulated glucose oxidase (GOx) with a coating of hyaluronic acid (HA) modified with a nitric oxide donor (HN). In the proposed GOx@CMPB-HN nanoparticles, the dopant Cu2+ ions are crucial to combining and mutually promoting multiple therapeutic approaches, namely, CDT, photothermal therapy (PTT), and starvation therapy. The dopant Cu2+ ions in CMPB protect against reactive oxygen species to deplete the intracellular GSH in the TME. Additionally, the byproduct Cu+ ions act as a substrate for a Fenton-like reaction that activates CDT. Moreover, H2O2, which is another important substrate, is produced in large quantities through intracellular glucose depletion caused by the nanoparticle-loaded GOx, and the gluconic acid produced in this reaction further enhances the TME acidity and creates a better catalytic environment for CDT. In addition, Cu2+ doping greatly improves the mesoporous Prussian blue (MPB) photothermal conversion performance, and the resultant increase in temperature accelerates CDT catalysis. Finally, the HN coating enables the nanoparticles to actively target CD44 receptors in cancer cells and also enhances vascular permeability. Therefore, this coating has multiple effects, such as facilitating enhanced permeability and retention and deep laser penetration. In vitro and in vivo experiments demonstrate that the proposed GOx@CMPB-HN nanoplatform significantly inhibits tumor growth with the help of in situ enhanced synergistic therapies based on the properties of the TME. The developed nanoplatform has the potential to be applied to cancer treatment and introduces new avenues for tumor treatment research.

Biomimetic nanozyme with natural enzyme-like activities has drawn extensive attention in cancer therapy, while its application was hindered by the limited catalytic efficacy in the complicated tumor microenvironment (TME). Herein, a hybrid biomimetic nanozyme combines polydopamine-decorated CuO with a natural enzyme of glucose oxidase (GOD), among which CuO is endowed with a high loading rate (47.1%) of GOD due to the elaborately designed hollow mesoporous structure that is constructed to maximize the cascade catalytic efficacy. In the TME, CuO could catalyze endogenous H2O2 into O2 for relieving tumor hypoxia and improving the catalytic efficacy of GOD. Whereafter, the amplified glucose oxidation induces starvation therapy, and the generated H2O2 and H+ enhance the catalytic activity of CuO. Significantly, the tumor-specific chemodynamic therapy (CDT) could be realized when CuO degraded into Cu2+ in acidic and reductive TME. Furthermore, the photothermal therapy with high photothermal conversion efficiency (30.2%) is achieved under NIR-II laser (1064 nm) excitation, which could reinforce the generation of reactive oxygen species (•OH and •O2-). The TME initiates the biochemical reaction cycle of CuO, O2, and GOD, which couples with an NIR-II-induced thermal effect to realize O2-promoted starvation and photothermal-chemodynamic combined therapy. This hybrid biomimetic nanozyme enlightens the further development of nanozymes in multimodal cancer therapy.

Glucose oxidase (GOD)-mediated starvation therapy (ST) that causes intratumoral glucose depletion is a promising strategy for tumor treatment. However, the ultimate efficacy is inevitably limited by tumor hypoxia, as oxygen is a key component in the consumption of glucose by GOD. In this study, a kind of glutathione (GSH)-responsive organosilica hybrid micelles loaded with Mn3 O4 and GOD (denoted as Mn3 O4 @PDOMs-GOD) is ingeniously designed for enhanced ST and chemodynamic therapy (CDT). Specifically, the internalized Mn3 O4 @PDOMs-GOD in tumor cells consumes intracellular glucose and oxygen (O2 ) under the catalysis of GOD to generate hydrogen peroxide (H2 O2 ), which is subsequently decomposed by Mn3 O4 to liberate O2 . This cyclically regenerated O2 will form a virtuous cycle of O2 and H2 O2 compensation to enhance the ST outcome. Meanwhile, Mn3 O4 can oxidize and deplete the overexpressed GSH in the tumor microenvironment (TME) to release Mn2+ , which then catalyzes H2 O2 into highly toxic hydroxyl radicals (·OH) to accomplish chemodynamic therapy (CDT). Both in vitro and in vivo experiment results demonstrate the significant antitumor efficacy of Mn3 O4 @PDOMs-GOD by the cooperatively enhanced ST and CDT, suggesting the feasibility to develop promising therapeutic platforms with higher treatment efficacies.

MoS2-ALG-Fe/GOx hydrogel with Fenton catalytic activity for combined cancer photothermal, starvation, and chemodynamic therapy

Starvation therapy kills tumor cells via consuming glucose to cut off their energy supply. However, since glucose oxidase (GOx)-mediated glycolysis is oxygen-dependent, the cascade reaction based on GOx faces the challenge of a hypoxic tumor microenvironment. By decomposition of glycolysis production of H2 O2 into O2 , starvation therapy can be enhanced, but chemodynamic therapy is limited. Here, a close-loop strategy for on demand H2 O2 and O2 delivery, release, and recycling is proposed. The nanoreactor (metal-protein-polyphenol capsule) is designed by incorporating two native proteins, GOx and hemoglobin (Hb), in polyphenol networks with zeolitic imidazolate framework as sacrificial templates. Glycolysis occurs in the presence of GOx with O2 consumption and the produced H2 O2 reacts with Hb to produce highly cytotoxic hydroxyl radicals (•OH) and methemoglobin (MHb) (Fenton reaction). Benefiting from the different oxygen carrying capacities of Hb and MHb, oxygen on Hb is rapidly released to supplement its consumption during glycolysis. Glycolysis and Fenton reactions are mutually reinforced by oxygen supply, consuming more glucose and producing more hydroxyl radicals and ultimately enhancing both starvation therapy and chemodynamic therapy. This cascade nanoreactor exhibits high efficiency for tumor suppression and provides an effective strategy for oxygen-mediated synergistic starvation therapy and chemodynamic therapy.

It is a viable strategy to develop a safer and tumor-specific method by considering the tumor microenvironment to optimize the curative effect and reduce the side effects in cancer treatment. In this study, glucose oxidase (GOx) and Fe3O4 nanoparticles were successfully loaded inside regenerated silk fibroin/zein (RSF/zein) nanospheres to obtain dual-loaded Fe3O4/GOx@RSF/zein nanospheres. The unique structure of the RSF/zein nanospheres reported in our previous work was favorable to loading sufficient amounts of GOx and Fe3O4 nanoparticles in the nanospheres. For Fe3O4/GOx@RSF/zein nanospheres, GOx depletes endogenous glucose via an enzyme-catalyzed bioreaction, simultaneously generating plenty of H2O2in situ. It was further catalyzed through a Fe3O4-mediated Fenton reaction to form highly toxic hydroxyl free radicals (˙OH) in the acidic tumor microenvironment. These two successive reactions made up the combination of starvation therapy and chemodynamic therapy during cancer treatment. The catalytic activity of GOx loaded in the RSF/zein nanospheres is similar to that of the pristine enzyme. It was maintained for more than one month due to the protection of the RSF/zein nanospheres. The methylene blue degradation results confirmed the sequential reaction by GOx and Fe3O4 from Fe3O4/GOx@RSF/zein nanospheres. The in vitro experiments demonstrated that the Fe3O4/GOx@RSF/zein nanospheres entered MCF-7 cells and generated ˙OH free radicals. Therefore, these Fe3O4/GOx@RSF/zein nanospheres exhibited a considerable synergistic therapeutic effect. They showed more efficient suppression in cancer cell growth than either single-loaded GOx@RSF/zein or Fe3O4@RSF/zein nanospheres, achieving the design goal for the nanospheres. Therefore, the Fe3O4/GOx@RSF/zein nanospheres cut off the nutrient supply due to the strong glucose dependence of tumor cells and generated highly toxic ˙OH free radicals in tumor cells, effectively enhancing the anticancer effect and minimizing side effects. Therefore, in future clinical applications, the Fe3O4/GOx@RSF/zein nanospheres developed in this study have significant potential for combining starvation and chemodynamic therapy.

Tumor microenvironment (TME)-activatable phototheranostics is highly desirable in cancer management but still remains challenging for clinical applications owing to the lack of multifunctional theranostic agents and the limited tissue penetration depth. Reported here is an "all-in-one" phototheranostic platform based on near-infrared II (NIR-II) dual-plasmonic Au@Cu2-x Se core-shell nanocrystals (dpGCS NCs) for combined photoacoustic (PA)/photothermal (PT) imaging-guided chemodynamic therapy (CDT)/photocatalytic therapy (PCT)/photothermal therapy (PTT) all triggered by a single NIR-II laser. The dpGCS NCs feature excellent NIR-II plasmonic and PT properties, which guarantee their capabilities of NIR-II PA and PT imaging for real-time visual observation of tumor size and location during cancer treatment. Additionally, the TME-activated in situ •OH production via dpGCS NC-catalyzed Fenton-like reaction is further enhanced by the NIR-II irradiation, while photoexcited plasmonic hole-induced formation of extra •OH is also evidenced for PCT. Both in vitro and in vivo experiments confirm remarkable therapeutic efficacy of the present phototheranostic platform under NIR-II laser through the CDT/PCT/PTT trimodal combination therapy, achieving complete inhibition of tumor growth in tumor-bearing mice after administration of dpGCS NCs plus a single NIR-II laser irradiation. This work provides a distinctive paradigm for the development of NIR-II phototheranostic platforms for imaging-guided cancer therapy using a single laser.

Near-infrared light-triggered synergistic antitumor therapy based on hollow ZIF-67-derived Co3S4-indocyanine green nanocomplex as a superior reactive oxygen species generator

Recent advances in multifunctional nanomaterials for photothermal-enhanced Fenton-based chemodynamic tumor therapy.

Biodegradable nanotherapeutic with simultaneously GSH depletion and H2O2 supplying for enhanced synergistic chemotherapy/chemodynamic therapy

Sustainable amorphous Fenton nanosystem for visualization-guided synergistic tumor elimination