H2S-Responsive NIR-II Fluorescent Nanozyme that Regulates Tumor Microenvironment for Activatable Synergistic CO Therapy/Catalytic Therapy/Immunotherapy.

Nanozyme catalytic therapy triggered by the tumor microenvironment (TME)-responsive enzyme-like catalytic activities is an emerging approach for tumor treatment. However, the poor catalytic efficiency of nanozymes in tumors and the toxic side effects on normal tissues limit their further development, primarily due to the limited uptake and penetration depth of nanozyme in tumor tissues. Here, a tumor-targeting TME and electric field stimuli-responsive nanozyme (AgPt@CaCO3-FA) is developed, which is capable of catalyzing the generation of ROS to induce cell death and releasing carbon monoxide (CO) specifically in tumor tissues for on-demand CO therapy and immunotherapy. Benefiting from the endogenous H2S activated NIR-II fluorescence (FL) imaging guidance, AgPt@CaCO3-FA can be delivered into the deeper site of tumor tissues resulted from the TME regulation via generated CO during the electrolysis process to improve the catalytic efficiency of nanozymes in tumors. Moreover, CO effectively relieve immunosuppression TME via reeducating tumor-supportive M2-like macrophages to tumoricidal M1-like macrophages and induce mitochondrial dysfunction by reducing mitochondrial membrane potential, triggering tumor cells apoptosis. The enzyme-like activities combined with CO therapy arouse distinct immunogenic cell death (ICD) effect. Therefore, AgPt@CaCO3-FA permits synergistic CO gas, catalytic therapy and immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence.

Transition-metal-based nanozymes for biosensing and catalytic tumor therapy.

Nanozymes, as an emerging class of enzyme mimics, have attracted much attention due to their adjustable catalytic activity, low cost, easy modification, and good stability. Researchers have made great efforts in developing and applying high-performance nanozymes. Recently, transition-metal-based nanozymes have been designed and widely developed because they possess unique photoelectric properties and high enzyme-like catalytic activities. To highlight these achievements and help researchers to understand the research status of transition-metal-based nanozymes, the development of transition-metal-based nanozymes from material characteristics to biological applications is summarized. Herein, we focus on introducing six categories of transition-metal-based nanozymes and highlight their progress in biomarker sensing and catalytic therapy for tumors. We hope that this review can guide the further development of transition-metal-based nanozymes and promote their practical applications in cancer diagnosis and treatment.

Tensile Strain-Mediated Bimetallene Nanozyme for Enhanced Photothermal Tumor Catalytic Therapy.

Nanozymes have demonstrated significant potential in combating malignant tumor proliferation through catalytic therapy. However, the therapeutic effect is often limited by insufficient catalytic performance. In this study, we propose the utilization of strain engineering in metallenes to fully expose the active regions due to their ultrathin nature. Here, we present the first report on a novel tensile strain-mediated local amorphous RhRu (la-RhRu) bimetallene with exceptional intrinsic photothermal effect and photo-enhanced multiple enzyme-like activities. Through geometric phase analysis, electron diffraction profile, and X-ray diffraction, it is revealed that crystalline-amorphous heterophase boundaries can generate approximately 2 % tensile strain in the bimetallene. The ultrathin structure and in-plane strain of the bimetallene induce an amplified strain effect. Both experimental and theoretical evidence support the notion that tensile strain promotes multiple enzyme-like activities. Functioning as a tumor microenvironment (TME)-responsive nanozyme, la-RhRu exhibits remarkable therapeutic efficacy both in vitro and in vivo. This work highlights the tremendous potential of atomic-scale tensile strain engineering strategy in enhancing tumor catalytic therapy.

Bridging the Catalytic Turnover Gap Between Single-Atom Iron Nanozymes and Natural Enzymes by Engineering the First and Second Shell Coordination.

Single-atom nanozymes (SAzymes) constitute a promising category of enzyme-mimicking materials with outstanding catalytic performance. The performance of SAzymes improves through modification of the coordination environments around the metal center. However, the catalytic turnover rates of SAzymes, which are key measures of the effectiveness of active site modifications, remain lower than those of natural enzymes, especially in peroxidase-reactions. Here, the first and second shell coordination tuning strategy that yields SAzymes with structures and activities analogous to those of natural enzymes is reported. The optimized SAzyme exhibits a turnover rate of 52.7 s-1 and a catalytic efficiency of 6.97 × 105 M-1 s-1. A computational study reveals that axial S-ligands induce an alternative reaction mechanism, and SO2- functional groups provide hydrogen bonds to reduce the activation energy. In addition, SAzyme shows superior anti-tumor ability in vitro and in vivo. These results demonstrate the validity of coordination engineering strategies and the carcinostatic potential of SAzymes.

Engineering Atomically Dispersed Cu-N1S2 Sites via Chemical Vapor Deposition to Boost Enzyme-Like Activity for Efficient Tumor Therapy.

Single-atom nanozymes (SAzymes), with well-defined and uniform atomic structures, are an emerging type of natural enzyme mimics. Currently, it is important but challenging to rationally design high-performance SAzymes and deeply reveal the interaction mechanism between SAzymes and substrate molecules. Herein, this work reports the controllable fabrication of a unique Cu-N1S2-centred SAzyme (Cu-N/S-C) via a chemical vapor deposition-based sulfur-engineering strategy. Benefiting from the optimized geometric and electronic structures of single-atom sites, Cu-N/S-C SAzyme shows boosted enzyme-like activity, especially in catalase-like activity, with a 13.8-fold increase in the affinity to hydrogen peroxide (H2O2) substrate and a 65.2-fold increase in the catalytic efficiency when compared to Cu-N-C SAzyme with Cu-N3 sites. Further theoretical studies reveal that the increased electron density around single-atom Cu is achieved through electron redistribution, and the efficient charge transfer between Cu-N/S-C and H2O2 is demonstrated to be more beneficial for the adsorption and activation of H2O2. The as-designed Cu-N/S-C SAzyme possesses an excellent antitumor effect through the synergy of catalytic therapy and oxygen-dependent phototherapy. This study provides a strategy for the rational design of SAzymes, and the proposed electron redistribution and charge transfer mechanism will help to understand the coordination environment effect of single-atom metal sites on H2O2-mediated enzyme-like catalytic processes.

Multiple therapeutic mechanisms of pyrrolic N-rich g-C3N4 nanosheets with enzyme-like function in the tumor microenvironment.

Nanozyme-based synergistic catalytic therapies for tumors have attracted extensive research attention. However, the unsatisfactory efficiency and negative impact of the tumor microenvironment (TME) hinder its clinical applications. In this study, we provide an easy method to prepare transition metals loaded onto pyrrolic nitrogen-rich g-C3N4 (PN-g-C3N4) for forming metal-N4 sites. This N-rich material effectively transfers electrons from g-C3N4 to metal-N4 sites, promotes the oxidation-reduction reaction of metals with different valence states, and improves material reusability. Under TME conditions, copper ions loaded onto PN-g-C3N4 (Cu-PN-g-C3N4, CPC) can produce ·OH through a Fenton-like reaction for tumor inhibition. This Fenton-like reaction and tumor cell inhibition can be improved further by a photodynamic effect caused by light irradiation. We introduced upconversion nanoparticles (UCNPs) into CPC to obtain nano-enzymes (UCNPs@Cu-PN-g-C3N4, UCPC) for effectively penetrating the tissue, which emits light corresponding to the UV absorption region of CPC when excited with 980 nm near-infrared (NIR) light. The nanoplatform can reduce H2O2 concentration upon exposure to NIR light; this induces an increase in dissolved oxygen content and produces a higher supply of reactive oxygen species (ROS) for destroying tumor cells. Owing to the narrow bandgap (1.92 eV) of UCPC under 980 light irradiation, even under the condition of hypoxia, the excited electrons in the conduction band can reduce insoluble O2 through a single electron transfer process, thus effectively generating O2•-. Nanoenzyme materials with catalase properties produce three types of ROS (·OH, O2•- and 1O2) when realizing chemodynamic and photodynamic therapies. An excellent therapeutic effect was established by killing cells in vitro and the tumor-inhibiting effect in vivo, proving that the prepared nanoenzymes have an effective therapeutic effect and that the endogenous synergistic treatment of multiple treatment technologies can be realized.

Bioinspired Structure Regulation of Apyrase-Like Nanozyme with Intracellular-Generated H2O2 for Tumor Catalytic Therapy.

Adenosine triphosphate (ATP) is the major resource of energy supply in tumor activity. Therefore, improving ATP consumption efficiencies is a promising approach for cancer therapy. Herein, inspired by the H2O2-involved structure regulation effect during the catalysis of natural protein enzymes, we developed an artificial H2O2-driven ATP catalysis-promoting system, the Ce-based metal-organic framework (Ce-MOF), for catalytic cancer therapy. In the presence of H2O2, the hydrolysis ATP activity of Ce-MOF(H2O2) was enhanced by around 1.6 times. Taking advantage of the endogenous H2O2 in cancerous cells, catalytic hydrolysis for intracellular ATP of the Ce-MOF achieves the inhibition of cancerous cell growth, which involves damaged mitochondrial function and autophagy-associated cell death. Furthermore, in vivo studies suggest that the Ce-MOF has a good tumor inhibition effect. The artificial H2O2-driven ATP catalysis-promoting system not only demonstrates high catalytic ATP consumption efficiencies for cancer therapy but also highlights a bioinspired strategy to expedite nanozyme research in both design and applied sciences.

Nanoheterojunction-Mediated Thermoelectric Strategy for Cancer Surgical Adjuvant Treatment and ß-Elemene Combination Therapy.

As an indispensable strategy for tumor treatment, surgery may cause two major challenges: tumor recurrence and wound infection. Here, a thermoelectric therapeutic strategy is provided as either an independent cancer therapy or surgical adjuvant treatment. Bi0.5 Sb1.5 Te3 (BST) and Bi2 Te2.8 Se0.2 (BTS) nanoplates composed of Z-scheme thermoelectric heterojunction (BST/BTS) are fabricated via a two-step hydrothermal processes. The contact between BST and BTS constructs an interfacial electric field due to Fermi energy level rearrangement, guiding electrons in the conductive band (CB) of BTS combine with the holes in the valance band (VB) of BST, leaving stronger reduction/oxidation potentials of electrons and holes in the CB of BST and the VB of BTS. Moreover, under a mild temperature gradient, another self-built-in electric field is formed facilitating the migration of electrons and holes to their surfaces. Based on the PEGylated BST/BTS heterojunction, a novel thermoelectric therapy platform is developed through intravenous injection of BST/BTS and external cooling of the tumors. This thermoelectric strategy is also proved effective for combination cancer therapy with ß-elemene. Moreover, the combination of heterojunction and hydrogel is administrated on the wound after surgery, achieving efficient residual tumor treatment and antibacterial effects.

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

The field of nanomedicine-catalyzed tumor therapy has achieved a lot of progress; however, overcoming the limitations of the tumor microenvironment (TME) to achieve the desired therapeutic effect remains a major challenge. In this study, a nanocomposite hydrogel (GH@LDO) platform combining the nanozyme CoMnFe-layered double oxides (CoMnFe-LDO) and natural enzyme glucose oxidase (GOX) was engineered to remodel the TME to enhance tumor catalytic therapy. The CoMnFe-LDO is a nanozyme that can convert endogenous H2O2 into reactive oxygen species (ROS) and O2 to achieve chemodynamic therapy (CDT) and alleviate the hypoxic microenvironment. Meanwhile, GOX can catalyze the conversion of glucose and O2 to gluconic acid and H2O2, which not only represses the ATP production of tumor cells to achieve starvation therapy (ST), but also decreases the pH value of TME and supplies extra H2O2 to enhance the CDT effect. Furthermore, this well-designed CoMnFe-LDO possessed a high photothermal conversion efficiency of GH@LDO (66.63%), which could promote the generation of ROS to enhance the CDT effect and achieve photothermal therapy (PTT) under near-infrared light irradiation. The GH@LDO hydrogel performes cascade reaction which overcomes the limitation of the TME and achieves satisfactory CDT/ST/PTT synergetic effects in vitro and in vivo. This work provides a new strategy for remodeling the TME using nanomedicine to achieve precise tumor cascaded catalytic therapy. STATEMENT OF SIGNIFICANCE: At present, the focus of tumor therapy has begun to shift from monotherapy to combination therapy for improving the overall therapeutic effect. In this study, we synthesized a CoMnFe-LDO nanozyme composed of multiple transition metal oxides, which demonstrated improved peroxidase and oxidase activities as well as favorable photothermal conversion capability. The CoMnFe-LDO nanozyme was compounded with an injectable GH hydrogel crosslinked by GOX and horseradish peroxidase (HRP). This nanocomposite hydrogel overcame the limitations of weak acidity, H2O2, and O2 levels in the TME and achieved synergetic CDT, ST, and PTT effects based on the cascaded catalytic actions of CoMnFe-LDO and GOX to H2O2 and glucose.

Tumor microenvironment-activated single-atom platinum nanozyme with H2O2 self-supplement and O2-evolving for tumor-specific cascade catalysis chemodynamic and chemoradiotherapy.

Nanozyme-based tumor collaborative catalytic therapy has attracted a great deal of attention in recent years. However, their cooperative outcome remains a great challenge due to the unique characteristics of tumor microenvironment (TME), such as insufficient endogenous hydrogen peroxide (H2O2) level, hypoxia, and overexpressed intracellular glutathione (GSH). Methods: Herein, a TME-activated atomic-level engineered PtN4C single-atom nanozyme (PtN4C-SAzyme) is fabricated to induce the "butterfly effect" of reactive oxygen species (ROS) through facilitating intracellular H2O2 cycle accumulation and GSH deprivation as well as X-ray deposition for ROS-involving CDT and O2-dependent chemoradiotherapy. Results: In the paradigm, the SAzyme could boost substantial ∙OH generation by their admirable peroxidase-like activity as well as X-ray deposition capacity. Simultaneously, O2 self-sufficiency, GSH elimination and elevated Pt2+ release can be achieved through the self-cyclic valence alteration of Pt (IV) and Pt (II) for alleviating tumor hypoxia, overwhelming the anti-oxidation defense effect and overcoming drug-resistance. More importantly, the PtN4C-SAzyme could also convert O2·- into H2O2 by their superior superoxide dismutase-like activity and achieve the sustainable replenishment of endogenous H2O2, and H2O2 can further react with the PtN4C-SAzyme for realizing the cyclic accumulation of ∙OH and O2 at tumor site, thereby generating a "key" to unlock the multi enzymes-like properties of SAzymes for tumor-specific self-reinforcing CDT and chemoradiotherapy. Conclusions: This work not only provides a promising TME-activated SAzyme-based paradigm with H2O2 self-supplement and O2-evolving capacity for intensive CDT and chemoradiotherapy but also opens new horizons for the construction and tumor catalytic therapy of other SAzymes.