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Objectives: Natural enzymes mouthwash has been proposed as salivary substitutes to treat xerostomia. This study aims to evaluate the efficacy of the mouthwash to treat xerostomia., Materials and Methods: A double-blind, parallel group randomised control clinical trial involving N = 49 adult participants with xerostomia was carried out. Intervention group received natural enzymes moisturising mouthwash (with active ingredients lactoferrin, lysozyme, lactoperoxidase and glucose oxidase); while control group received benzydamine mouthwash. Mouthwashes were repacked, labelled with specific code, and were given to participants by third-party. Subjects were instructed to rinse with the mouthwash 4 times per day at a specific period, for 2 weeks. Symptoms of xerostomia were assessed using Xerostomia Inventory at day 0 and 14; together with the assessment of Clinical Oral Dryness Score (CODS), and measurement of resting and stimulated salivary flow rate., Results: 48 participants completed the clinical follow-up, and n = 1 had lost of follow-up. From the 48 participants, n = 23 received natural enzymes mouthwash, while n = 25 received benzydamine mouthwash. Intervention group achieved reduction in symptoms of xerostomia from baseline. Intervention group also showed significantly better improvements in the cognitive perception of dry mouth and oromotor function such as chewing, swallowing and speech of the participants; and reduction in waking up at night to drink water (p < 0.05). The CODS and resting salivary flow rate were also significantly improved in intervention group (p < 0.05)., Conclusion: Use of natural enzymes mouthwash improved signs and symptoms of xerostomia., Clinical Relevance: Natural enzymes mouthwash is potentially effective to treat xerostomia, well-tolerated and safe to be used by xerostomia patients., Clinical Trial Registration Number: This study was retrospectively registered in ClinicalTrials.gov ID NCT05640362 on 7 December 2022., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Simultaneous lactate metabolism inhibition and intracellular acidification (LIIA) is a promising approach for inducing tumor regression by depleting ATP. However, given the limited efficacy of individual metabolic modulators, a combination of various modulators is required for highly efficient LIIA. Herein, a co-delivery system that combines lactate transporter inhibitor, glucose oxidase, and O 2 -evolving nanoparticles is proposed. As a vehicle, a facile room-temperature synthetic method for large-pore mesoporous silica nanoparticles (L-MSNs) is developed. O 2 -evolving nanoparticles are then conjugated onto L-MSNs, followed by immobilizing the lactate transporter inhibitor and glucose oxidase inside the pores of L-MSNs. To load the lactate transporter inhibitor, which is too small to be directly loaded into the large pores, it is encapsulated in albumin by controlling the albumin conformation before being loaded into L-MSNs. Notably, inhibiting lactate efflux shifts the glucose consumption mechanism from lactate metabolism to glucose oxidase reaction, which eliminates glucose and produces acid. This leads to synergistic LIIA and subsequent ATP depletion in cancer cells. Consequently, L-MSN-based co-delivery of modulators for LIIA shows high anticancer efficacy in several mouse tumor models without toxicity in normal tissues. This study provides new insights into co-delivery of small-molecule drugs, proteins, and nanoparticles for synergistic metabolic modulation in tumors., (© 2023 Wiley-VCH GmbH.)

Nanomaterial-based cancer therapy faces significant limitations due to the complex nature of the tumor microenvironment (TME). Starvation therapy is an emerging therapeutic approach that targets tumor cell metabolism using glucose oxidase (GOx). Importantly, it can provide a material or environmental foundation for other diverse therapeutic methods by manipulating the properties of the TME, such as acidity, hydrogen peroxide (H 2 O 2 ) levels, and hypoxia degree. In recent years, this cascade strategy has been extensively applied in nanoplatforms for ongoing synergetic therapy and still holds undeniable potential. However, only a few review articles comprehensively elucidate the rational designs of nanoplatforms for synergetic therapeutic regimens revolving around the conception of the cascade strategy. Therefore, this review focuses on innovative cascade strategies for GOx-based synergetic therapy from representative paradigms to state-of-the-art reports to provide an instructive, comprehensive, and insightful reference for readers. Thereafter, we discuss the remaining challenges and offer a critical perspective on the further advancement of GOx-facilitated cancer treatment toward clinical translation.

Reactive oxygen species (ROS)-involved tumor therapeutic strategy, chemodynamic therapy (CDT), has attracted extensive research interest in the scientific community. However, the therapeutic effect of CDT is insufficient and unsustainable owing to the limited endogenous H 2 O 2 level in the tumor microenvironment. Here, peroxidase (POD)-like RuTe 2 nanozyme with the immobilization of glucose oxidase (GOx) and allochroic 3,3',5,5'-tetramethylbenzidine (TMB) molecule have been synthesized to construct RuTe 2 -GOx-TMB nanoreactors (RGT NRs) as cascade reaction systems for tumor-specific and self-replenishing cancer therapy. GOx in sequential nanocatalysts can effectively deplete glucose in tumor cells. Meanwhile, a sustainable supply of H 2 O 2 for subsequent Fenton-like reactions catalyzed by RuTe 2 nanozyme is achieved in response to the mild acidic tumor microenvironment. Through this cascade reaction, highly toxic hydroxyl radicals (·OH) are produced, which can further oxidize TMB to trigger tumor-specific "turn-on" photothermal therapy (PTT). In addition, PTT and massive ROS can stimulate the tumor immune microenvironment and activate the systematic anti-tumor immune responses, exerting a notable effect on hindering tumor recurrence and metastasis. This study paves a promising paradigm for synergistic starvation therapy, PTT, and CDT cancer therapy with high efficiency., (© 2023 Wiley-VCH GmbH.)

Diabetic ulcers have received much attention in recent years due to their high incidence and mortality, motivating the scientific community to develop various strategies for such chronic disease treatments. However, the therapeutic outcome of these approaches is highly compromised by invasive bacteria and a severe inflammatory microenvironment. To overcome these dilemmas, microenvironment-responsive self-delivery glucose oxidase@manganese sulfide (GOx@MnS) nanoparticles (NPs) are developed by one-step biomineralization. When they encounter the high glucose level in the ulcer site, GOx particles catalyze glucose to decrease the local pH and trigger the steady release of both manganese ions (Mn 2+ ) and hydrogen sulfide (H 2 S). Mn 2+ reacts with hydrogen peroxide to generate hydroxyl radicals for the elimination of bacterial infection; meanwhile, H 2 S is able to suppress the inflammatory response and accelerate diabetic wound healing through macrophage polarization. The excellent biocompatibility, strong bactericidal activity, and considerable immunomodulatory effect promise GOx@MnS NPs have great therapeutic potential for diabetic wound treatment.

Bacterial biofilms, especially ones caused by multi-drug resistant strains, are increasingly posing a significant threat to human health. Inspired by nature, we report the fabrication of glucose oxidase-loaded iron-phenolic networks that can power the cascade reaction to generate free radicals to eradicate bacterial biofilms. A soft template, sodium deoxycholate, is employed to guarantee glucose oxidase activity during encapsulation, yielding the porous nanocomplexes after removing the template. The porous nature of nanocomplexes, characterized via transmission electron microscopy, N 2 adsorption isotherms, and thermogravimetric analysis, facilitates the diffusion of substrates and products during the cascade reaction and protects glucose oxidase from protease attack. Our optimized nanocomplexes (Fe-GA/GOx) could efficiently kill drug-resistant ESKAPE pathogens, including the clinically isolated strains and eradicate their biofilms. In this regard, Fe-GA/GOx could induce over 90% of the biomass of Klebsiella pneumoniae and Staphylococcus aureus biofilms. In the murine peritonitis infection model induced by Staphylococcus aureus and pneumonia model induced by Klebsiella pneumoniae, our Fe-GA/GOx nanocomplexes could efficiently eradicate the bacteria (over 3-log reduction in colony-forming units) and alleviate the inflammatory response without notable side effects on normal tissues. Therefore, our strategy may provide an efficient alternative treatment to combat bacterial biofilms and address the emergence of drug resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Protein therapy has been considered to be one of the most direct and safe ways to regulate cell function and treat tumors. However, safe and effective intracellular delivery of protein drugs is still a key challenge. Herein, we developed a tannic acid-assisted biomineralization strategy for the encapsulation and intracellular delivery of protein drugs. RNase A and glucose oxidase (GOD) were choose as the protein drug model. RNase A, GOD, TA, and Mn 2+ are mixed in one pot to attain RG@MT, and CaCO 3 coating is subsequently carried out to construct RG@MT@C through biomineralization. Once RG@MT@C is endocytosed, the acidic environment of the lysosome will dissolve the protective layer of CaCO 3 and produce plenty of CO 2 to cause lysosome bursting, ensuring the lysosome escape of the RG@MT@C and thus releasing the generated TA-Mn 2+ , RNase A, and GOD into the cytoplasm. The released substances would activate starvation therapy, chemodynamic therapy, and protein therapy pathways to ensure a high performance of cancer therapy. Due to simple preparation, low toxicity, and controlled release in the tumor microenvironment, we expect it can realize efficient and nondestructive delivery of protein drugs and meet the needs for precise, high performance of synergistically antitumor therapy in biomedical applications.

Notwithstanding immune checkpoint blocking (ICB) therapy has made eminent clinical breakthroughs, overcoming immunologically "cold" tumors remains challenging. Here, a cascade potentiated nanomodulator AuPtAg-GOx is engineered for boosting immune responsiveness. Upon 1064 nm laser irradiation, AuPtAg-mediated mild photothermal therapy (PTT) activates cytotoxic T lymphocytes and reverses the immunogenic "cold" tumor microenvironment. Further, to amplify the thermal sensitivity of tumor cells, glucose oxidase (GOx) is introduced to suppress the production of heat shock proteins, thereby promoting mild photothermal therapy. Complementarily, AuPtAg nanozymes with catalase-like activity can ameliorate tumor hypoxia, significantly improving the GOx activity. As a result, the combination of AuPtAg-GOx with self-augmented photothermal ability and PD-L1 antibody can further escalate the antitumor efficacy. The AuPtAg-GOx-based synergistic starvation therapy, mild PTT, and immunotherapy cascade enhancement therapy strategy can be a favorable tool to effectively kill cancer cells., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Activated fibroblast-like synovial (FLS) cells are regarded as an important target for rheumatoid arthritis (RA) treatment via starvation therapy mediated by glucose oxidase (GOx). However, the hypoxic RA-FLS environment greatly reduces the oxidation process of glucose and leads to a poor therapeutic effect of the GOx-based starvation therapy. In this work, we designed a hollow mesoporous copper sulfide nanoparticles (CuS NPs)-based smart GOx/atovaquone (ATO) codelivery system (named as V-HAGC) targeting RA-FLS cells to realize a O 2 -economized dual energy inhibition strategy to solve the limitation of GOx-based starvation therapy. V-HAGC armed with dual multi-stimuli-responsive "doorkeepers" can guard drugs intelligently. Once under the stimulation of photothermal and acidic conditions at the targeted area, the dual intelligent responsive "doors" would orderly open to realize the controllable release of drugs. Besides, the efficacy of V-HAGC would be much improved by the additional chemodynamic therapy (CDT) and photothermal therapy (PTT) stimulated by CuS NPs. Meanwhile, the upregulated H 2 O 2 and acid levels by starvation therapy would promote the Fenton-like reaction of CuS NPs under O 2 -economized dual energy inhibition, which could enhance the PTT and CDT efficacy as well. In vitro and in vivo evaluations revealed V-HAGC with much improved efficacy of this combination therapy for RA. In general, the smart V-HAGC based on the O 2 -economized dual energy inhibition strategy combined with enhanced CDT and PTT has the potential to be an alternative methodology in the treatment of RA.

Poor tumor specificity is one of the key obstacles for clinical applications of nanotheranostic agents, consequently leading to serious side effects and unsatisfactory therapeutic efficacy. Herein, biomolecule-based nanohybrids (named as Hb-PDA-GOx) with multiple stimuli-responsiveness were designed and fabricated to enhance tumor-specific therapy. The nanohybrids embodied two proteins, i.e., hemoglobin (Hb) and glucose oxidase (GOx), which exhibited cascade catalytic activity selectively within the tumor microenvironment (TME). Specifically, GOx catalyzes the overexpressed glucose into gluconic acid and hydrogen peroxide (H 2 O 2 ), which not only initiated starvation therapy (ST) through cutting off the nutrition supply for carcinoma cells, but also provided H 2 O 2 for sequential Fenton reaction induced by Hb that generating biotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). Moreover, localized heat generation from polydopamine (PDA) in the nanohybrids can implement photothermal therapy (PTT) and reinforce the CDT efficacy. Excitingly, effective eradication of solid tumors and significant suppression of metastatic tumors growth were achieved by utilizing Hb-PDA-GOx as a versatile theranostic agent. All these results had been verified by in vitro and/or in vivo experiments. In light of the superior anticancer effects and insignificant systemic toxicity, the as-fabricated biomolecule-based nanohybrids could be employed as a promising agent for tumor-specific therapy. More importantly, the high biocompatibility and biodegradability of the selected biomolecules would facilitate subsequent clinical translation. STATEMENT OF SIGNIFICANCE: (1) A facile one-pot synthesis strategy was proposed to fabricate biomolecule-based tumor theranostic agent with high biocompatibility and biodegradability, which would facilitate subsequent clinical translation; (2) The as-developed theranostic agent was endowed with multiple stimuli-responsiveness for achieving tumor-specific and cascade-enhanced synergistic therapy; (3) The in vivo experiments demonstrated that the as-developed theranostic agent can not only effectively eradicate solid tumors, but also significantly suppress metastatic tumors growth., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Nanotechnology has shown a revolution in cancer treatments, including breast cancers. However, there remain some challenges and translational hurdles. Surgery, radiotherapy, and chemotherapy are the primary treatment methods for breast cancer, although drug combinations showed promising results in preclinical studies. Herein we report the development of a smart drug delivery system (DDS) to efficiently treat breast cancer by pyroptosis-starvation-chemotherapeutic combination. Cancer-starvation agent glucose oxidase was chemically attached to synthesized iron oxide nanoparticles which were entrapped inside poly(lactic- co -glycolic acid) along with apoptosis-associated speck-like protein containing a caspase recruitment domain plasmid and paclitaxel (PTX). An emulsion solvent evaporation method was used to prepare the DDS. The surface of the DDS was modified with chitosan to which aptamer was attached to achieve site-specific targeting. Hence, the prepared DDS could be targeted to a tumor site by both external magnet and aptamer to obtain an enhanced accumulation of drugs at the tumor site. The final size of the aptamer-decorated DDS was less than 200 nm, and the encapsulation efficiency of PTX was 76.5 ± 2.5%. Drug release from the developed DDS was much higher at pH 5.5 than at pH 7.4, ensuring the pH sensitivity of the DDS. Due to efficient dual targeting of the DDS, in vitro viability of 4T1 cells was reduced to 12.1 ± 1.6%, whereas the nontargeted group and free PTX group could reduce the viability of cells to 29.2 ± 2.4 and 46.2 ± 1.6%, respectively. Our DDS showed a synergistic effect in vitro and no severe side effects in vivo. This DDS has strong potential to treat various cancers.

A hyaluronic acid (HA)-based one-pot hydrogel reactor with single syringe injection and immediate gelation was developed for starvation therapy (ST), chemodynamic therapy (CDT), ferroptosis, and photothermal therapy (PTT) against breast cancer. A rheologically tuned hydrogel network, composed of HA-phenylboronic acid (HP) and HA-dopamine (HD), was designed by introducing a boronate ester linkage (phenylboronic acid-dopamine interaction) and polydopamine bond (pH control). Ferrocene (Fc)-conjugated HP (Fc-HP) was synthesized to achieve ferroptosis, Fenton reaction-involved toxic hydroxyl radical ( • OH) generation, and photothermal ablation in cancer therapy. Glucose oxidase (GOx) was entrapped in the pH-modulated Fc-HP (Fc-HP°)/HD hydrogel network for converting intracellular glucose to H 2 O 2 to enable its own supply. The GOx/Fc combination-installed hydrogel reactor system can provide sustained ST/CDT/PTT functions along with ferroptosis. Injection of Fc-HP°/HD/GOx hydrogel with single-syringe injectability, shear-thinning feature, and self-healing capability offered a slow biodegradation rate and high safety profiles. Peritumorally injected Fc-HP°/HD/GOx hydrogel also efficiently suppressed the growth of breast cancer based on multifunctional therapeutic approaches with reduced dosing frequency. Hyperthermia induced by near-infrared (NIR) laser absorption may amplify the therapeutic effects of free radicals. It is expected that this Fc-HP°/HD/GOx hydrogel system can be applied to local cancer therapy with high efficacy and safety profiles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cancer cells rely on glycolysis to support a high proliferation rate. Metformin (Met) is a promising drug for tumor treatment that targets hexokinase 2 (HK2) to block the glycolytic process, thereby further disrupting the metabolism of cancer cells. Herein, an intelligent nanomedicine based on glucose deprivation and glycolysis inhibition is creatively constructed for enhanced cancer synergistic treatment. In brief, Met and glucose oxidase (GOx) was encapsulated into histidine/zeolitic imidazolate framework-8 (His/ZIF-8), which was followed by coating with Arg-Gly-Asp (RGD) peptides to obtain the desired nanomedicine (Met/GOx@His/ZIF-8∼RGD). This smart nanomedicine presents the controllable Met and GOx release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. According to in vitro and in vivo assays, the combination of glycolysis inhibition and starvation therapy demonstrates efficient cancer cells growth suppression and superior antitumor properties compared to the Met based or GOx-mediated monotherapy. This work provides an advanced therapeutic strategy via disrupting cellular metabolism against cancer. STATEMENT OF SIGNIFICANCE: The obtained nanomedicine (Met/GOx@His/ZIF-8∼RGD) presents the controllable Met and glucose oxidase (GOx) release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. The combination of glycolysis inhibition and starvation therapy demonstrate the efficient suppression of cancer cells growth and the superior antitumor properties when compared to the Met based or GOx-mediated monotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Inhibited immune response and low levels of delivery restrict starvation cancer therapy efficacy. Here, we report on the co-delivery of glucose oxidase (GOx) and indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan using a metal-organic framework (MOF)-based nanoreactor, showing an amplified release for tumor starvation/oxidation immunotherapy. The nanosystem significantly overcomes the biobarriers associated with tumor penetration and improves the cargo bioavailability owing to the weakly acidic tumor microenvironment-activated charge reversal and size reduction strategy. The nanosystem rapidly disassembles and releases cargoes in response to the intracellular reactive oxygen species (ROS). GOx competitively consumes glucose and generates ROS, further inducing the self-amplifiable MOF disassembly and drug release. The starvation/oxidation combined IDO-blockade immunotherapy not only strengthens the immune response and stimulates the immune memory through the GOx-activated tumor starvation and recruitment of effector T cells, but also effectively relieves the immune tolerance by IDO blocking, remarkably inhibiting the tumor growth and metastasis in vivo., (© 2022. The Author(s).)

Sequential nano-catalytic therapy has emerged as a novel therapeutic modality for cancer treatment as it utilizes the unique tumor microenvironment for selective tumor treatment. This study reports a magnetic nanoparticle to achieve Fenton-like reaction and dual-imaging guidance/monitoring. Natural glucose oxidase (GOx) and superparamagnetic Fe 3 O 4 nanoparticles have been integrated into poly(lactic- co -glycolic acid) (PLGA) to fabricate a sequential nanocatalyst (designated as GOx@PLGA-Fe 3 O 4 ). This nanocatalyst can functionally deplete glucose in tumor tissues, producing a considerable amount of highly cytotoxic hydroxyl radicals via the sequential Fenton-like reaction, and meanwhile maximizing the potential imaging capability as a contrast agent for magnetic resonance imaging and photoacoustic imaging. By ribonucleic acid sequencing (RNA-seq) technology, GOx@PLGA-Fe 3 O 4 nanoparticles are demonstrated to induce tumor cell death by inhibiting multiple gene regulation pathways involving tumor growth and recurrence. Therefore, this finding provides a novel strategy to achieve promising therapeutic efficacy by the rational design of multifunctional nanoparticles with various features, including magnetic targeting, sequential nano-catalytic therapy, and dual-imaging guidance/monitoring.

Organic near-infrared fluorescent dye mediated photothermal therapy (PTT) and photodynamic therapy (PDT) suffer from heat shock response, since, heat shock proteins (HSPs) are overexpressed and can repair the proteins damaged by PTT and PDT. Starvation therapy by glucose oxide (GOx) can inhibit the heat shock response by limiting the energy supply. However, the delivery of sufficient and active GOx remains a challenge. To solve this problem, we utilize liposomes as drug carriers and prepare GOx loaded liposome (GOx@Lipo) with a high drug loading content (12.0%) and high enzymatic activity. The successful delivery of GOx shows excellent inhibition of HSPs and enhances PTT and PDT. Additionally, we apply the same liposome formulation to load near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbo cyanine iodide (DiR) and prepare DiR contained liposomes (DiR@Lipo) for PTT and PDT. The liposomal formulation substantially enhances the PTT and PDT properties of DiR as well as the cellular uptake and tumor accumulation. Finally, the combination therapy shows excellent tumor inhibition on 4T1 tumor-bearing mice. Interestingly, we also find that the starvation therapy can efficiently inhibit tumor metastasis, which is probably due to the immunogenic effect. Our work presents a biocompatible and effective carrier for the combination of starvation therapy and phototherapy, emphasizing the importance of auxiliary starvation therapy against tumor metastasis and offering important guidance for clinical PTT and PDT.

Companion diagnostics (CDx) provides critical information for precision medicine. However, current CDx is mostly limited to in vitro tests, which cannot accurately evaluate the disease progression and treatment response in real time. To overcome this challenge, herein a glucose oxidase (GOx)-engineered conjugated polymer (polyaniline, PANI) nanoplatform (denoted as PANITG) is reported for activatable imaging-based CDx and multistage augmented photothermal/starvation synergistic therapy. PANITG comprises a pH-activatable conjugated polymer as a photothermal convertor and photoacoustic (PA) emitter, a GOx as a cancer starvation inducer as well as a H 2 O 2 and acid producer, and a H 2 O 2 -cleavable linker as a "switch" for GOx activity. The in vivo PA imaging and photothermal therapy abilities are activated by acidic tumor microenvironment and self-augmented by the reaction between GOx and glucose. Meanwhile, the photothermal effect will enhance the GOx activity in turn. Such multistage augmentation of the therapeutic effects will facilitate effective cancer management. In addition, the in vivo PA imaging with PANITG reveals the tumor pH level which is correlated to the efficiency of the photothermal therapy and to the catalytic activity of GOx at each stage, enabling real-time activatable CDx., (© 2022 Wiley-VCH GmbH.)

The emergence of peroxidase (POD)-like nanozyme-derived catalytic therapy has provided a promising choice for reactive oxygen species (ROS)-mediated broad-spectrum antibacterials to replace antibiotics, but it still suffers from limitations of low therapeutic efficiency and unusual addition of unstable H 2 O 2 . Considering that the higher blood glucose in diabetic wounds provides much more numerous nutrients for bacterial growth, a cascade nanoenzymatic active material was developed by coating glucose oxidase (GOx) onto POD-like Fe 2 (MoO 4 ) 3 [Fe 2 (MoO 4 ) 3 @GOx]. GOx could consume the nutrient of glucose to produce gluconic acid (weakly acidic) and H 2 O 2 , which could be subsequently converted into highly oxidative • OH via the catalysis of POD-like Fe 2 (MoO 4 ) 3 . Accordingly, the synergistic effect of starvation and ROS-mediated therapy showed significantly efficient antibacterial effect while avoiding the external addition of H 2 O 2 that affects the stability and efficacy of the therapy system. Compared with the bactericidal rates of 46.2-59.404% of GOx or Fe 2 (MoO 4 ) 3 alone on extended-spectrum β-lactamases producing Escherichia coli and methicillin-resistant Staphylococcus aureus , those of the Fe 2 (MoO 4 ) 3 @GOx group are 98.396 and 98.776%, respectively. Animal experiments showed that the as-synthesized Fe 2 (MoO 4 ) 3 @GOx could much efficiently promote the recovery of infected wounds in type 2 diabetic mice while showing low cytotoxicity in vivo .

Biomimetic drug delivery systems offer new opportunities to mimic biological components for enhancing tumor targeting efficiency and promoting therapeutic efficacy. Therefore, in this study, the platelet exosomes and photothermal sensitive liposomes were coalesced and incorporated glucose oxidase (GOx, G) and ferric ammonium (FAC, F) to constitute a laser controlled nanosystem (FG@PEL). Results confirmed that FG@PEL possessed two cascade therapeutic strategies. As the first cascade therapeutic strategy, FG@PEL had achieved cascade targeting effect due to the inheritance of biological property of platelet exosomes to adhere cancer cells and respond on the vascular damage triggered by photothermal effect. Subsequently, GOx was used to oxidize glucose to produce hydrogen peroxide which could be catalyzed by FAC to realize cascade reaction for enhancing chemodynamic therapy (CDT). Meanwhile, photothermal effect could accelerate the reaction rate to further improve the therapeutic effect by producing more hydroxyl radicals. So significant therapeutic effect could be acquired through the synergistic modality of FG@PEL, and the mechanism of mutual promotion among different treatment was also clarified. Hence, this research may provide a promising strategy for curative tumor therapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Starvation-dependent differential stress sensitization effect between normal and tumor cells provides a potentially promising strategy to amplify chemotherapy effects and reduce side effects. However, the conventional starvation approaches such as glucose oxidase (Gox)-induced glucose depletion and nanomedicine-enabled vascular embolism usually suffer from aggravated tumor hypoxia, systemic toxicity, and unpredictable metabolic syndrome. Herein, a novel "valve-closing" starvation strategy is developed to amplify the chemotherapy effects via closing the "valve" of glucose transported into tumor cells, which is accomplished by a glucose transporters 1 (GLUT1, valve of glucose uptake) inhibitor (Genistein, Gen) and chemotherapeutic agent (Curcumin, Cur) coloaded hybrid organosilica-micelles nanomedicine (designated as (Gen + Cur)@FOS) with controllable stability. In vitro and in vivo results demonstrate that (Gen + Cur)@FOS can effectively reduce glucose/adenosine triphosphate levels in tumor cells by inhibiting GLUT1 expression (i.e., "valve-closing") to induce the starvation of tumor cells, thus weakening the resistance of tumor cells to apoptosis caused by chemotherapy, and consequently contributing to the remarkably improved antitumor efficiency and minimized side effects based on the stress sensitization effect mediated by GLUT1 inhibition-induced starvation. This "valve-closing" starvation strategy provides a promising paradigm for the development of novel nanotherapeutics with amplified chemotherapy effect., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

A nanoscale therapeutic system with good biocompatibility was facilely fabricated by the coassembly of human serum albumin and glucose oxidase (GOD), where the former was pretreated with metal ions through a chelating agent or the chemotherapeutic prodrug oxaliplatin (Oxa(IV)). Among different chelating metal ions used, Mn 2+ ion was selected to produce hydroxyl radical (•OH) efficiently through Fenton-like reaction, while GOD loaded in the system was able to generate a large amount of hydrogen peroxide for promoting efficient conversion into highly toxic •OH. In the meanwhile, the conversion of the Oxa(IV) prodrug into chemotherapeutic Oxa(II) was beneficial for the consumption of glutathione, thereby enhancing the chemodynamic therapy (CDT) efficacy. Based on the combined chemotherapy and CDT, the treatment with this system leads to superior antitumor outcome.

Nanozymes have been combined with glucose oxidase (GOx) for dual-enzyme cascade catalytic therapy. However, their catalysis efficiency is restricted because of the hypoxia tumor microenvironment (TME). Although many methods are developed for O 2 supply, the O 2 leakage and consumption of H 2 O 2 compromised their practical application. Herein, a biocompatible carbon nitride (C 3 N 4 )/nanozyme/GOx triple cascade nanocatalyst was designed with laser-activatable O 2 self-supply via water splitting to relieve tumor hypoxia and thus improve the catalysis efficiency. To this end, polydopamine (PDA) nanosphere was prepared and attached with C 3 N 4 nanosheet to improve water splitting efficiency and realize photothermal-enhanced catalysis, simultaneously. The PDA@C 3 N 4 composite was then coated with MIL-100 (Fe), where GOx was loaded, to form C 3 N 4 /MIL-100/GOx triple cascade nanocatalyst. The triple cascade catalysis was realized with laser-activatable O 2 supply from PDA@C 3 N 4 , H 2 O 2 generation with GOx, and •OH production from peroxidase-like MIL-100 (Fe) for tumor therapy. Upon 808 nm irradiation, PDA, as a photothermal agent, realized photothermal therapy and enhanced the catalytic therapy. Thus, the synergy of laser-activatable O 2 supply and photothermal enhancement in our triple cascade nanocatalyst improved the performance of catalytic therapy without drug resistance and toxicity to normal tissues., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multimodal nanotherapeutic cancer treatments are widely studied but are often limited by their costly and complex syntheses that are not easily scaled up. Herein, a simple formulation of glucose-oxidase-coated CuS nanoparticles was demonstrated to be highly effective for melanoma treatment, acting through a synergistic combination of glucose starvation, photothermal therapy, and synergistic advanced chemodynamic therapy enabled by near-infrared irradiation coupled with Fenton-like reactions that were enhanced by endogenous chloride.

Nanozyme has been regarded as one of the antibacterial agents to kill bacteria via a Fenton-like reaction in the presence of H 2 O 2 . However, it still suffers drawbacks such as insufficient catalytic activity in near-neutral conditions and the requirement of high H 2 O 2 levels, which would minimize the side effects to healthy tissues. Herein, a mesoporous ceria hollow sphere/enzyme nanoreactor is constructed by loading glucose oxidase in the mesoporous ceria hollow sphere nanozyme. Due to the mesoporous framework, large internal voids, and high specific surface area, the obtained nanoreactor can effectively convert the nontoxic glucose into highly toxic hydroxyl radicals via a cascade catalytic reaction. Moreover, the generated glucose acid can decrease the localized pH value, further boosting the peroxidase-like catalytic performance of mesoporous ceria. The generated hydroxyl radicals could damage severely the cell structure of the bacteria and prevent biofilm formation. Moreover, the in vivo experiments demonstrate that the nanoreactor can efficiently eliminate 99.9% of bacteria in the wound tissues and prevent persistent inflammation without damage to normal tissues in mice. This work provides a rational design of a nanoreactor with enhanced catalytic activity, which can covert glucose to hydroxyl radicals and exhibits potential applications in antibacterial therapy.

Glucose oxidase (GOx) is regarded as an ideal endogenous natural enzyme for tumor starvation therapy and photothermal therapy (PTT) is a promising strategy for the ablation of primary tumor. In this work, Cu-doped cobalt oxide and porous carbon nanocomposites (CuCo(O)@PCNs) were synthesized from double-layered ZIF-8@ZIF-67 and GOx was loaded in the porous carbon to form a CuCo(O)/GOx@PCNs hybrid nanozyme. CuCo(O) was characterized as the Cu 0.3 Co 2.7 O 4 phase through X-ray diffraction analysis and it can react with H 2 O 2 to generate O 2 and alleviate tumor hypoxia, resulting in the recovered enzymatic activity of GOx and the enhanced starvation therapy. The porous nanocarbon can ablate the primary tumor because of its high photothermal conversion efficiency of 40.04%. The three-in-one functions of oxygen supply, glucose consumption, and photothermal conversion were realized in the ZIFs-derived CuCo(O)/GOx@PCNs nanozyme and the starvation therapy effect was improved by PTT and oxygen supplement. Furthermore, the inhibition effect of CuCo(O)/GOx@PCNs on metastatic tumor is similar to combined therapy of the nanozyme and the immune checkpoint-blocking antibody, α-PD-1. The related antitumor immune mechanism was studied through the analysis of immune-related proinflammatory cytokines and the activated T cells. This work may provide new ideas for the development and application of the ZIFs-derived hybrid nanozyme in tumor therapy and the CuCo(O)/GOx@PCNs nanozyme may be a promising alternative to immune checkpoint inhibitors.

Ultrasound (US)-induced sonodynamic therapy (SDT) is an efficient and precise method against tumor, and the integration of multiple cancer therapies has been proved as a promising strategy for better therapeutic effects. Herein, for the first time, a multifunctional nanoreactor has been fabricated by integrating Fe-MIL-88B-NH 2 , PFC-1, and glucose oxidase (GO x ) to form urchin-like Fe-MIL-88B-NH 2 @PFC-1-GO x (MPG) nanoparticles as Fenton's reagent, a sonosensitizer, and a tumor microenvironment (TME) modulator. In detail, MPG can generate • OH for chemodynamic therapy (CDT) and deplete glutathione (GSH) to alleviate the antioxidant ability of cancer cells. Moreover, catalase (CAT)-like MPG can react with H 2 O 2 to generate O 2 for relieving hypoxia in TME, enhancing GO x -catalyzed glucose oxidation to produce H 2 O 2 and gluconic acid. Then, the regenerated H 2 O 2 can promote the Fenton reaction to achieve GO x catalysis-enhanced CDT. Owing to its large π-electron conjugated system, MPG also serves as an ideal sonosensitizer, realizing a burst generation of 1 O 2 under US irradiation for efficient SDT. Therefore, the tumor treatment will be notably enhanced by MPG-based synergetic CDT/SDT/starvation therapy via a series of cascade reactions. Overall, this work develops a versatile nanoreactor with improved tumor treatment effectiveness and broadens the application prospects of porous materials in the field of biomedical research.

The common existence of hypoxia within the tumor microenvironment severely restricts the efficacy of photodynamic therapy (PDT), which is attributed to the fact that the PDT process is strongly oxygen (O2) dependent. Here, a multifunctional composite (named CPCG), which combines polyethylene glycol (PEG) functionalized cerium oxide nanoparticles (CeO2) with photosensitizer chlorin e6 (Ce6) and glucose oxidase (GOx), is reported for generating O2 within the tumor microenvironment by the dual-path hydrogen peroxide (H2O2)-modulated ways to ameliorate hypoxia, thereby enhancing the PDT efficiency. This process is realized based on the dual enzyme-like activity of CeO2. The first modulated way is to transform the superoxide anion (O2˙-) into H2O2 by the superoxide dismutase-like activity of CeO2. The second modulated way is to decompose glucose into H2O2 through the catalysis of GOx. Subsequently, H2O2 generated from the above dual modulated ways can further produce O2via the catalase-like activity of CeO2. Additionally, the depletion of glucose could impede the nutrient supply to obtain starvation therapy. Both in vitro and in vivo experiments indicate that the CPCG composite could enhance the efficacy of photodynamic/starvation synergistic therapy. Therefore, this strategy offers great potential to modulate the O2 level in the tumor microenvironment for better therapeutic outcomes, and can act as a promising candidate in photodynamic/starvation synergistic therapy.

Developing new strategies to enhance drug accumulation in the tumor and therapeutic efficacy is of great importance in the field of tumor therapy. Herein, a peanut-like multifunctional nanomedicine (CuS-PGH NMs) made of CuS nanoparticles encapsulated in poly(l-lysine)(PLL)/glucose oxidase (GOx)-hyaluronic acid (HA) shells has been constructed via layer-by-layer (LbL) assembly, and shows good biocompatibility and effective multi-gradient therapy. Because of the enhanced permeability and retention (EPR) effect, the CuS-PGH NMs could significantly enhance the cellular uptake by tumors overexpressing CD44 receptors, which respond to hyaluronidase (HAase)-triggered surface charge conversion. Once internalized by the tumor, GOx was the first to be exposed and could effectively deplete endogenous glucose for starvation therapy, and the excess H2O2 was then converted into highly toxic hydroxyl radicals (˙OH) via a Cu+-mediated Fenton-like reaction for chemodynamic therapy (CDT). Meanwhile, the as-obtained Cu+ ions accompanied the regenerated less-active Cu2+ ions. Interestingly, the high content of H2O2 could, in turn, accelerate Cu2+/Cu+ conversion to promote the Cu+-H2O2 reaction for enhanced chemodynamic therapy (CDT), thereby achieving efficient tumor growth suppression via synergistic starvation/CDT therapy. Subsequently, owing to the strong NIR-II absorption capability of CuS-PGH NMs, effective photothermal tumor ablation of the weakened tumor cells could be realized with the precise guidance of NIR-II PAI. This multi-gradient therapeutic strategy has been demonstrated to have excellent antitumor activity with minimal nonspecific damages, and offers a new avenue to precise tumor therapy.

Inspired by the particularity of tumor microenvironments, including acidity and sensibility to reactive oxygen species (ROS), advanced and smart responsive nanomaterials have recently been developed. The present study synthesized tumor-targeted and pH-sensitive supramolecular micelles that self-assembled via host-guest recognition. The micelles consumed intratumoral glucose and lactate via loading with glucose oxidase (GOD) and lactate oxidase (LOD). Intratumoral glucose and lactate were converted into hydrogen peroxide (H 2 O 2 ) and were sequentially reduced to highly toxic hydroxyl radicals ( • OH) via the peroxidase (POD)-like activity of the loaded C-dot nanozymes. Tumor-killing effects were observed via cascade catalytic reactions. After an intravenous injection, the nanocomposite exhibited an excellent tumor-targeted ability with good biocompatibility, which demonstrated its effective antitumor effect. The nanocomposite effectively combined starvation and catalytic therapies and exerted a synergistic anticancer effect with minimal side effects and without external addition.

The clinical effectiveness and scar quality of the randomized controlled trial comparing enzyme alginogel with silver sulfadiazine (SSD) for treatment of partial thickness burns were previously reported. Enzyme alginogel did not lead to faster wound healing (primary outcome) or less scar formation. In the current study, the health-related quality of life (HRQoL), costs, and cost-effectiveness of enzyme alginogel compared with SSD in the treatment of partial thickness burns were studied. HRQoL was evaluated using the Burn Specific Health Scale-Brief (BSHS-B) and the EQ-5D-5L questionnaire 1 week before discharge and at 3, 6, and 12 months postburn. Costs were studied from a societal perspective (health care and nonhealth-care costs) for a follow-up period of 1 year. A cost-effectiveness analysis was performed using cost-effectiveness acceptability curves and comparing differences in societal costs and Quality Adjusted Life Years (QALYs) at 1 year postburn. Forty-one patients were analyzed in the enzyme alginogel group and 48 patients in the SSD group. None of the domains of BSHS-B showed a statistically significant difference between the treatment groups. Also, no statistically significant difference in QALYs was found between enzyme alginogel and SSD (difference -0.03; 95% confidence interval [CI], -0.09 to 0.03; P = .30). From both the health care and the societal perspective, the difference in costs between enzyme alginogel and SSD was not statistically significant: the difference in health-care costs was €3210 (95% CI, €-1247 to €7667; P = .47) and in societal costs was €3377 (95% CI €-6229 to €12 982; P = .49). The nonsignificant differences in costs and quality-adjusted life-years in favor of SSD resulted in a low probability (<25%) that enzyme alginogel is cost-effective compared to SSD. In conclusion, there were no significant differences in quality of life between both treatment groups. Enzyme alginogel is unlikely to be cost-effective compared with SSD in the treatment of partial thickness burns., (© 2020 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound Healing Society.)

The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu 2 MoS 4 (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo-dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu 1+/2+ , Mo 4+/6+ ) exhibit Fenton-like, glutathione (GSH) peroxidase-like and catalase-like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton-like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase-like CMS could react with endogenous H 2 O 2 to generate O 2 for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H 2 O 2 . The regenerated H 2 O 2 can devote to Fenton-like reaction for realizing GOx-catalysis-enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor-killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O 2 - ) generation performance. More importantly, the PEGylated CMS@GOx-based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Targeted activation or enhancement is an attractive strategy in the design of nano-theranostics. However, the responsiveness of the nanoagents is restricted by the limited levels of intra-tumor stimuli. Herein, we constructed a positive feedback nanoamplifier by encapsulating glucose oxidase (GOx) in the ferric ions contained metal organic framework (MIL-100), and coating the nanoparticles with polydopamine modified hyaluronic acid (HA-PDA). The mechanism of action of the ensuing nanoamplifiers was three pronged: 1) the high intra-tumor acidity accelerated the release of GOx, which consumed endogenous glucose and "starved" the tumors, in addition to aggravating the local acidity and H 2 O 2 levels; 2) the hydroxyl radicals (·OH) generated from the Fenton-like reaction between MIL-100 with H 2 O 2 contributed to the chemodynamic tumor therapy and augmented the O 2 microenvironment, which could be speeded up under acid condition; 3) the oxygen (O 2 ) produced in the Fenton-like reaction relieved the intra-tumor hypoxia and ensured the enzymatic reaction of GOx, along with augmenting the photoacoustic signal of nanoamplifier. Preliminary experiments in tumor bearing mice showed that the nanoamplifier not only boosted the local acidity/H 2 O 2 /O 2 levels in tumor site to successfully suppress the growth of tumors through the self-enhanced chemodynamic/starving therapy, but also achieved the photoacoustic imaging of tumors. Taken together, this novel nanoamplifier with the abilities of self-enhanced tumor imaging and therapy is a promising entrant in the field of anti-tumor theranostics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Plaque accumulation and white spot lesions are common adverse effects of fixed orthodontic appliance use. This study compared the effects between enzyme-containing and conventional dentifrices on orthodontic patients. This double-blind randomized controlled trial included 42 orthodontic patients (25 women and 17 men: 22.7 ± 4.2 years) from Taipei Medical University Hospital between 2017 and 2018. The patients were randomly divided into three groups and assigned to dentifrice use during the first 3 months of the orthodontic treatment: group 1 used dentifrices containing enzymes including amyloglucosidase and glucose oxidase, group 2 used dentifrices containing 1450 ppm fluoride, and group 3 used natural dentifrices containing no chemical agent. White spot lesion index (WSL), gingival bleeding index (GBI), and visible plaque index (VPI) were recorded and analyzed. WSL, GBI, and VPI values exhibited no significant difference among the three groups. WSL increased significantly in group 3, GBI decreased significantly in all groups, and VPI decreased significantly in groups 1 and 2. No significant difference was observed between the use of enzyme-containing and conventional dentifrices after fixed orthodontic appliance placement.

Although partial thickness burns are the most frequently reported burn injuries, there is no consensus on the optimal treatment. The objective of this study was to compare the clinical effectiveness and scar quality of Flaminal® Forte to silver sulfadiazine (Flamazine®) in the treatment of partial thickness burns. In this two-arm open label multicenter randomized controlled trial, adult patients with acute partial thickness burns and an affected total body surface area of less than 30% were randomized between Flaminal® Forte and Flamazine® and followed for 12 months. Dressing changes in the Flamazine® group were performed daily, and in the Flaminal® group during the first 3 days post burn and thereafter every other day until complete wound healing or surgery. Forty-one patients were randomly allocated to Flaminal® Forte and 48 patients to Flamazine®. The primary outcome was time to wound healing, which did not differ between the groups: median 18 days with Flaminal® Forte (range 8-49 days) versus 16 days with Flamazine® (range 7-48 days; p = 0.24). Regarding the secondary outcomes during hospital admission, there were no statistically significant differences between the groups concerning need for surgery, pain scores, pruritus, or pain-related and anticipatory anxiety. More patients in the Flaminal® group developed wound colonization (78% versus 32%, p < 0.001), but the treatment groups did not differ regarding the incidence of local infections and use of systemic antibiotics. In terms of scar quality, no statistically significant differences between both treatment groups were found regarding subjective scar assessment (Patient and Observer Scar Assessment Scale (POSAS)), scar melanin and pigmentation (DermaSpectrometer®), and scar elasticity and maximal extension (Cutometer®) during 12 month postburn. In conclusion, time to wound healing did not differ, but the use of Flaminal® Forte seemed favorable because less dressing changes are needed which lowers the burden of wound care., (© 2019 The Authors. Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of by the Wound Healing Society.)

We demonstrate a MnO2-based nanoreactor to achieve continuous oxygen generation and efficient conversion from glucose to singlet oxygen for combined photodynamic-starvation therapy.

Cancer cells possess some inherent characteristics, such as glucose-dependence and intolerance to heat and exogenous reactive oxygen species (ROS). In this study, a strategy has been developed to target these vulnerable weaknesses of cancer cells using glucose oxidase (GOx) and polydopamine (PDA) functionalized iron oxide nanoparticles (Fe 3 O 4 @PDA/GOx NPs). PDA is first deposited on the surfaces of iron oxide NPs through self-polymerization, and then GOx is covalently linked with PDA upon mixing the enzyme and Fe 3 O 4 @PDA under alkaline conditions. In this system, the PDA layer along with iron oxide NPs serves as a photothermal transfer material converting near infrared (NIR) radiation into heat. The covalently linked GOx can competitively consume glucose and spontaneously generate ROS H 2 O 2 that can be further converted by the iron oxide NPs into more toxic ˙OH, inducing apoptosis of cancer cells. The selective toxicity of Fe 3 O 4 @PDA/GOx NPs on cancer cells is demonstrated both in vitro and in vivo. In particular, a single injection rather than multiple doses results in significant suppression of tumors, and does not induce apparent histological lesions in the 4T1 tumor-bearing Balb/c mice. The versatility of the functionalization strategy reported in this study will contribute to developing efficient therapies for selective cancer treatment.

Glucose oxidase (GOx) is an endogenous oxido-reductase that is widely distributed in living organisms. Over recent years, GOx has attracted increasing interest in the biomedical field due to its inherent biocompatibility, non-toxicity, and unique catalysis against β-d-glucose. GOx efficiently catalyzes the oxidization of glucose into gluconic acid and hydrogen peroxide (H2O2), which can be employed by various biosensors for the detection of cancer biomarkers. Various cancer therapeutic strategies have also been developed based on the catalytic chemistry of GOx: (1) the consumption of glucose provides an alternative strategy for cancer-starvation therapy; (2) the consumption of oxygen increases tumor hypoxia, which can be harnessed for hypoxia-activated therapy; (3) the generation of gluconic acid enhances the acidity of the tumor microenvironment, which can trigger pH-responsive drug release; (4) the generation of H2O2 increases the levels of tumor oxidative stress, and the H2O2 can be converted into toxic hydroxyl radicals that can kill cancer cells upon exposure to light irradiation or via the Fenton reaction. More importantly, GOx can be combined with other enzymes, hypoxia-activated prodrugs, photosensitizers or Fenton's reagents, to generate multi-modal synergistic cancer therapies based on cancer starvation therapy, hypoxia-activated therapy, oxidation therapy, photodynamic therapy, and/or photothermal therapy. Such multi-modal approaches are anticipated to exert a stronger therapeutic effect than one therapeutic mode alone. Thus, maximizing the potential of GOx in a biomedical context will offer novel clinical solutions to diagnose and treat cancer. In this tutorial review, we introduce the recent advances of GOx in cancer diagnosis and treatment. We then emphasize the design principles and biomedical applications of GOx-based biosensors and cancer therapeutic approaches. Finally, we discuss the challenges and future prospects of GOx-based catalytic systems in biomedicine.

Tumor hypoxia is one of the major challenges for the treatment of tumors, as it may negatively affect the efficacy of various anticancer modalities. In this study, a tumor-targeted redox-responsive composite biocatalyst is designed and fabricated, which may combine tumor starvation therapy and low-temperature photothermal therapy for the treatment of oxygen-deprived tumors. The nanosystem was prepared by loading porous hollow Prussian Blue nanoparticles (PHPBNs) with glucose oxidase (GOx) and then coating their surface with hyaluronic acid (HA) via redox-cleavable linkage, therefore allowing the nanocarrier to bind specifically with CD44-overexpressing tumor cells while also exerting control over the cargo release profile. The nanocarriers are designed to enhance the efficacy of the hypoxia-suppressed GOx-mediated starvation therapy by catalyzing the decomposition of intratumoral hydroperoxide into oxygen with PHPBNs, and the enhanced glucose depletion by the two complementary biocatalysts may consequently suppress the expression of heat shock proteins (HSPs) after photothermal treatment to reduce their resistance to the PHPBN-mediated low-temperature photothermal therapies.

Objectives: The objective of this study is to determine the efficacy of GUM® Hydral versus Biotène® Oralbalance (both a mouthwash plus gel) on the subjective burden and clinical symptoms of patients with medication-induced xerostomia., Materials and Methods: Subjects (N = 40) with medication-induced xerostomia (minimum 4/10 mm visual analog scale [VAS]) were randomized to treatment with GUM Hydral or Biotène Oralbalance mouthwash, both with gel, for 28 days. Subjects then entered a 21-day wash-out period, before crossing over to the other treatment for 28 days. Outcomes measured included the VAS, German Oral Health Impact Profile (OHIPG)-14, Xerostomia Questionnaire (XQ), after-use questionnaire, and clinical parameters., Results: Both GUM Hydral and Biotène Oralbalance significantly (p < 0.05) reduced VAS, OHIPG-14 total score and single items, and XQ Part 1 (oral dryness, oral pain, taste loss) and Part 2 items. GUM Hydral also significantly reduced the XQ Part 1 dysphagia score, while Biotène Oralbalance significantly reduced the halitosis organoleptic score and plaque index. Significant increases in saliva secretion did not reach clinical relevance. No significant between-group differences were observed, apart from OHIPG-14 items "trouble pronouncing words" and "uncertainty" in favor of GUM Hydral. No adverse effects were reported., Conclusions: Both products effectively improve oral health and xerostomia-related quality of life. However, they cannot completely substitute the continuous in-mouth secretion of saliva, and symptomatic relief is temporary. Product selection will be based on personal preference., Clinical Relevance: Both products diminish xerostomic burden and should be part of the management strategy. Affected patients should be informed of these treatments, since no adverse effects were reported.

Tumor cells metabolize in distinct pathways compared with most normal tissue cells. The resulting tumor microenvironment would provide characteristic physiochemical conditions for selective tumor modalities. Here we introduce a concept of sequential catalytic nanomedicine for efficient tumor therapy by designing and delivering biocompatible nanocatalysts into tumor sites. Natural glucose oxidase (GOD, enzyme catalyst) and ultrasmall Fe 3 O 4 nanoparticles (inorganic nanozyme, Fenton reaction catalyst) have been integrated into the large pore-sized and biodegradable dendritic silica nanoparticles to fabricate the sequential nanocatalyst. GOD in sequential nanocatalyst could effectively deplete glucose in tumor cells, and meanwhile produce a considerable amount of H 2 O 2 for subsequent Fenton-like reaction catalyzed by Fe 3 O 4 nanoparticles in response to mild acidic tumor microenvironment. Highly toxic hydroxyl radicals are generated through these sequential catalytic reactions to trigger the apoptosis and death of tumor cells. The current work manifests a proof of concept of catalytic nanomedicine by approaching selectivity and efficiency concurrently for tumor therapeutics.The specific metabolism of cancer cells may allow for selective tumor therapeutics. Here, the authors show that a suitable combination of an enzyme and iron nanoparticles loaded on dendritic silica induces apoptosis of cancer cells in response to the glucose-reliant and mild acidic microenvironment.

Selectively cuting off the nutrient supply and the metabolism pathways of cancer cells would be a promising approach to improve the efficiency of cancer treatment. Here, a cancer targeted cascade bioreactor (designated as mCGP) was constructed for synergistic starvation and photodynamic therapy (PDT) by embedding glucose oxidase (GOx) and catalase in the cancer cell membrane-camouflaged porphyrin metal-organic framework (MOF) of PCN-224 (PCN stands for porous coordination network). Due to biomimetic surface functionalization, the immune escape and homotypic targeting behaviors of mCGP would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, mCGP was found to promote microenvironmental oxygenation by catalyzing the endogenous hydrogen peroxide (H 2 O 2 ) to produce oxygen (O 2 ), which would subsequently accelerate the decomposition of intracellular glucose and enhance the production of cytotoxic singlet oxygen ( 1 O 2 ) under light irradiation. Consequently, mCGP displayed amplified synergistic therapeutic effects of long-term cancer starvation therapy and robust PDT, which would efficiently inhibit the cancer growth after a single administration. This cascade bioreactor would further facilitate the development of complementary modes for spatiotemporally controlled cancer treatment.

Glucose is a key energy supplier and nutrient for tumor growth. Herein, inspired by the glucose oxidase (GOx)-assisted conversion of glucose into gluconic acid and toxic H 2 O 2 , a novel treatment paradigm of starving-like therapy is developed for significant tumor-killing effects, more effective than conventional starving therapy by only cutting off the energy supply. Furthermore, the generated acidic H 2 O 2 can oxidize l-Arginine (l-Arg) into NO for enhanced gas therapy. By using hollow mesoporous organosilica nanoparticle (HMON) as a biocompatible/biodegradable nanocarrier for the co-delivery of GOx and l-Arg, a novel glucose-responsive nanomedicine (l-Arg-HMON-GOx) has been for the first time constructed for synergistic cancer starving-like/gas therapy without the need of external excitation, which yields a remarkable H 2 O 2 -NO cooperative anticancer effect with minimal adverse effect., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The efficacy of stannous fluoride toothpastes is well established for reducing caries, plaque, and gingivitis and relieving the discomfort of dentin hypersensitivity. Management of dry mouth may include relief remedies in addition to usual oral hygiene methods to maintain oral health and improve quality of life. This 6-week, single-blind, randomized, two-period crossover clinical study was designed to evaluate the oral tolerance and potential of Enamelon® Preventive Treatment Gel (EPTG), with 0.4% stannous fluoride, to relieve subject-perceived dry-mouth symptoms in a self-reported dry-mouth population, after 14 days of use, compared to a marketed over-the-counter (OTC) artificial saliva gel product (Biotene® Oral Balance Gel [BOBG])., Methods: Following a 7-day washout period, 52 qualified subjects with self-reported dry-mouth symptoms received EPTG or BOBG for once-daily use for 14 days. All subjects brushed each morning and evening with a standard fluoride toothpaste (Sensodyne® ProNamel). Each evening and following brushing with the Sensodyne ProNamel, subjects used their assigned gel product (EPTG or BOBG) as directed. On Days 1, 8, and 15, subjects received an oral examination and assessed relief of dry-mouth symptoms using a product-performance questionnaire (PPQ). Procedures were repeated with the alternate product for another 14-day period, following a 7-day washout. Data for each efficacy endpoint were analyzed using crossover ANOVA model., Results: No treatment-related adverse events were reported in this study, and both products were well tolerated by the subjects. Compared to pre-study ratings of usual dry-mouth remedies, both BOBG and EPTG significantly reduced dry-mouth symptoms following 14 days of use. BOBG was statistically significantly better than EPTG in relieving many of the principal dry-mouth symptoms such as providing immediate relief, having an immediate moisturizing and immediate lubricating effect, feeling comfortable in the mouth, soothing the mouth, effectively lubricating the mouth, and protecting the mouth from drying out (P < .05). Compared with subjects' ratings of their usual dry-mouth remedies, EPTG also provided relief of several dry-mouth symptoms at both Days 8 and 15 (P < .05)., Conclusion: Based on subjective measures of dry mouth and compared with pre-study ratings of usual remedies, subjects perceived that EPTG helped to manage symptoms such as relieving the discomfort of dry mouth, immediately moisturizing and lubricating, effectively lubricating, protecting from drying out, and providing long-lasting moisturization and long-lasting lubrication, and was not irritating to dry-mouth tissues. BOBG, the positive control, was significantly better than EPTG in relieving dry-mouth symptoms over a 2-week period and was not irritating., Practical Implications: Patients with dry-mouth symptoms may benefit from daily use of a non-irritating, OTC fluoride preventive treatment gel product to relieve symptoms while also reducing the risks of developing dental caries, demineralization, dentin hypersensitivity, and gingivitis.

Stimuli-responsive devices that deliver drugs or imaging contrast agents in spatial-, temporal- and dosage-controlled fashions have emerged as the most promising and valuable platform for targeted and controlled drug delivery. However, implementing high performance of these functions in one single delivery carrier remains extremely challenging. Herein, we have developed a sequential strategy for developing glucose and magnetic-responsive microvesicle delivery system, which regulates the glucose levels and spatiotemporally controls the generation of nitric oxide gas free bubbles. It is observed that such injectable microvesicles loaded with enzyme and magnetic nanoparticles can firstly regulate hyperglycemic level based on the enzymatic reactions between glucose oxidase and glucose. In a sequential manner, concomitant magnetic field stimuli enhance the shell permeability while prompts the reaction between H2O2 and l-arginine to generate the gasotransmitters nitric oxide, which can be imaged by ultrasound and further delivered for diabetic nephropathy therapy. Therefore, magnetic microvesicles with glucose oxidase may be designed as a novel theranostic approach for restoring glucose homeostasis and spatiotemporally control NO release for maintaining good overall diabetic health., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The main components of oral malodor have been identified as volatile sulfur compounds (VSCs) including hydrogen sulfide (H2S) and methyl mercaptan (CH3SH). VSCs also play an important role in the progression of periodontal disease. The aim of the present study was to assess the effects of the single ingestion of a tablet containing 20 mg of lactoferrin, 2.6 mg of lactoperoxidase, and 2.6 mg of glucose oxidase on VSCs in the mouth., Method: Subjects with VSCs greater than the olfactory threshold in their mouth air ingested a test or placebo tablet in two crossover phases. The concentrations of VSCs were monitored at baseline and 10 and 30 min after ingestion of the tablets using portable gas chromatography., Results: Thirty-nine subjects were included in the efficacy analysis based on a full analysis set (FAS). The concentrations of total VSCs and H2S at 10 min were significantly lower in the test group than in the placebo group (-0.246 log ng/10 ml [95 % CI -0.395 to -0.098], P = 0.002; -0.349 log ng/10 ml; 95 % CI -0.506 to -0.192; P < 0.001, respectively). In the subgroup analysis, a significant difference in the concentration of total VSCs between the groups was also observed when subjects were fractionated by sex (male or female) and age (20-55 or 56-65 years). The reducing effect on total VSCs positively correlated with the probing pocket depth (P = 0.035)., Conclusions: These results suggest that the ingestion of a tablet containing lactoferrin, lactoperoxidase, and glucose oxidase has suppressive effects on oral malodor., Trial Registration: This trial was registered with the University Hospital Medical Information Network Clinical Trial Registry (number: UMIN000015140 , date of registration: 16/09/2014).

Background: Partial thickness burns are painful, difficult to manage and can have a negative effect on quality of life through scarring, permanent disfigurement and loss of function. The aim of burn treatment in partial thickness burns is to save lives, stimulate wound healing by creating an optimumly moist wound environment, to have debriding and analgesic effects, protect the wound from infection and be convenient for the patient and caregivers. However, there is no consensus on the optimal treatment of partial thickness wounds. Flaminal® and Flamazine® are two standard treatment options that provide the above mentioned properties in burn treatment. Nevertheless, no randomized controlled study has yet compared these two common treatment modalities in partial thickness burns. Thus, the aim of this study is to evaluate the clinical effectiveness, quality of life and cost-effectiveness of Flaminal® versus Flamazine® in the treatment of partial thickness burns., Methods/design: In this two-arm open multi-center randomized controlled trial, 90 patients will be randomized between Flaminal® and Flamazine® and followed for 12 months. The study population will consist of competent or temporarily non-competent (because of sedation and/or intubation) patients, 18 years of age or older, with acute partial thickness burns and a total body surface area (TBSA) of less than 30 %. The main study outcome is time to complete re-epithelialization (greater than 95 %). Secondary outcome measures include need for grafting, wound colonization/infection, number of dressing changes, pain and anxiety, scar formation, health-related quality of life (HRQoL), and costs., Discussion: This study will contribute to the optimal treatment of patients with partial thickness burn wounds and will provide evidence on the (cost-)effectiveness and quality of life of Flaminal® versus Flamazine® in the treatment of partial thickness burns., Trial Registration: Netherlands Trial Register NTR4486 , registered on 2 April 2014.

Purpose: This multicenter, randomized, parallel group study analyzed the effectiveness of an experimental oral gel, a commercially available oral rinse and a commercially available mouth spray versus water alone at relieving self-reported symptoms of dry mouth over a 28-day home use treatment period. The effects of the study treatments on dry mouth-related quality of life (QoL) were also investigated., Methods: Eligible subjects were stratified by dry mouth severity (mild, moderate or severe) and randomized to receive one of the study treatments. Prior to first use they completed a questionnaire designed to assess their baseline dry mouth-related QoL. Following first use and on Day 8 (2 hours post-treatment only) and Day 29, subjects completed the modified Product Performance and Attributes Questionnaire (PPAQ) I at 0.5, 1, 2 and 4 hours post-treatment. Subjects further assessed treatment performance using the PPAQ II questionnaire on Days 8 and 29 and the dry mouth-related QoL questionnaire on Day 29., Results: In 396 randomized subjects almost all comparisons of responses to PPAQ I, including those for the primary endpoint (response to PPAQ I Question 1 'Relieving the discomfort of dry mouth' after 2 hours on Day 29), were statistically significant in favor of active treatment groups versus water (P < 0.05). All comparisons of responses to PPAQ II on Days 8 and 29 were statistically significant in favor of active treatments versus water (P < 0.05). Moreover, nearly all comparisons for dry mouth-related QoL scores on Day 29 were statistically significant in favor of the active treatments versus water. All the dry mouth management strategies in this trial were well tolerated.

Acute external ear lesions: clinical aspects, assessment and management. We reviewed the literature concerning the assessment and the management of the external ear traumas, which is not very rich. Nevertheless, we outlined the practical attitudes in the four major conditions met: the auricular haematoma, the auricular perichondritis, the auricular laceration and auricular bums. All these pathologies must be promptly treated because there is a risk of perichondritis, which can destroy the cartilage and will result in a severely deformed ear. Auricular haematomas must be drained as soon as possible, lacerations with exposed cartilage must be stitched urgently, and burnt ears should be washed, coated with alginates (Flaminal@) and covered with a loose dressing. Antibioprophyl- axy should always be prescribed after a complete microbiological sampling.

This study assessed the effects on plaque in the absence of brushing of two twice-daily mouthrinses, one with an enzymatic-based formulation (Biotène) and one with an antimicrobial chlorhexidine-based formulation (Peridex), and sterile water. Plaque levels were assessed in 23 participants using a 4-day, nonbrushing plaque regrowth model after twice-daily rinsing with sterile water (negative control), the enzyme-based mouthrinse, or the chlorhexidine-based mouthrinse (positive control). Peridex showed significantly greater prevention of plaque regrowth when compared with water and the enzyme-based Biotène mouthrinse. After 4 days, the enzyme-based mouthrinse was associated with a small but nonsignificant reduction in plaque regrowth compared with water. This study confirmed that Peridex is effective at prevention of plaque regrowth. Twice-daily rinsing with a Biotène formula that contained enzymes showed a small but nonsignificant trend toward prevention of plaque regrowth versus rinsing with water.

Objective and Study Design: The clinical efficacy, safety, and acceptability of a new oral saliva equivalent (Novasial) administered four times daily in the treatment of xerostomia in various medical conditions was compared with that of oxygenated glycerol triester oral spray (Aequasyal) and a moisturizing spray (Biotene) in a 2-week, multicenter, randomized, crossover study. Assessment included patient-based evaluation of mouth dryness score (primary endpoint) with a visual analog scale (VAS), blinded assessment of the oral tissue condition by a four-point ordinal scale, and patient-based assessment of tolerability and acceptability., Results: At day 14, Novasial decreased oral mouth dryness by 19.5%, (12.5 ± 22.6 mm, P < .0001 versus baseline), versus 10% (6.6 ± 17.9 mm with Aequasyal, P < .0001 versus Baseline; and P < .0156 versus Novasial) and 13% (8.6 ± 18.9 mm) with Biotene (P < .0001 versus baseline). The 50% decrease in the primary endpoint was not achieved, and the overall efficacy of Novasial and Aequasyal were similar with respect to xerostomia. Novasial was preferred to Aequasyal and Biotene in alleviating taste alteration and chewing difficulty. Treatment compliance was higher with Novasial (P = .0014 versus Aequasyal). The treatments improved the oral condition with equal efficacy and were safe and well tolerated (VAS 72-77 mm)., Conclusions: Novasial was a safe, well-tolerated, and acceptable treatment in patients with xerostomia induced by various treatments or pathologic conditions., (Copyright © 2015 Elsevier Inc. All rights reserved.)