MicroRNA-Triggered Nanozymes Cascade Reaction for Tumor-Specific Chemodynamic Therapy

Off-target toxicity and insufficient hydroxyl radicals (^.OH) generation limit the further clinical application of nanozymes in chemodynamic therapy (CDT). Herein, we designed and constructed a microRNA-triggered nanozyme cascade platform for enhanced tumor-specific chemodynamic therapy. The nanozyme-based cascade reaction could be triggered successfully by the high expression of microRNA in cancer cells to generate more ^.OH, thus exhibiting excellent tumor-specific therapeutic performance. Our work provides a new dimension for tumor-specific chemodynamic therapy.     

CXCR4‐Targeted and MMP‐Responsive Iron Oxide Nanoparticles for Enhanced Magnetic Resonance Imaging

MRI offers high spatial resolution with excellent tissue penetration but it has limited sensitivity and the commonly administered contrast agents lack specificity. In this study, two sets of iron oxide nanoparticles (IONPs) were synthesized that were designed to selectively undergo copper‐free click conjugation upon sensing of matrix metalloproteinase (MMP) enzymes, thereby leading to a self‐assembled superparamagnetic nanocluster network with T₂ signal enhancement properties. For this purpose, IONPs with bioorthogonal azide and alkyne surfaces masked by polyethylene glycol (PEG) layers tethered to CXCR4‐targeted peptide ligands were synthesized and characterized. The IONPs were tested in vitro and T₂ signal enhancements of around 160 % were measured when the IONPs were incubated with cells expressing MMP2/9 and CXCR4. Simultaneous systemic administration of the bioorthogonal IONPs in tumor‐bearing mice demonstrated the signal‐enhancing ability of these ‘smart’ self‐assembling nanomaterials.     

A pH-responsive ultrathin Cu-based nanoplatform for specific photothermal and chemodynamic synergistic therapy

Noninvasive tumor therapy requires a new generation of bionanomaterials towards sensitive response to the unique tumor microenvironment to achieve accurate and effective treatment. Herein, we have developed a tumor therapy nanoplatform by immobilizing natural glucose oxidase (GOD) onto Cu-based layered double hydroxide (CuFe-LDH) nanosheets, which for the first time integrates acid-enhanced photothermal therapy (PTT), and pH-responsive and heat-facilitated chemodynamic therapy (CDT) simultaneously. As demonstrated by EXAFS and HRTEM, CuFe-LDH nanosheets possess a considerable number of defects caused by different acid conditions, resulting in a significantly acid-enhanced photothermal conversion efficiency (83.2% at pH 5.4 vs. 46.0% at pH 7.4). Moreover, GOD/CuFe-LDH nanosheets can convert a cascade of glucose into hydroxyl radicals (˙OH) under tumor acid conditions, which is validated by a high maximum velocity (V_max = 2.00 × 10⁻⁷ M) and low Michaelis–Menten constant (K_M = 12.01 mM). With the combination of PTT and CDT, the tumor tissue in vivo is almost eliminated with low-dose drug injection (1 mg kg⁻¹). Therefore, this novel pH-responsive Cu-based nanoplatform holds great promise in tumor-specific CDT/PTT synergistic therapy.

A pH-responsive multifunctional nanosystem was synthesized by loading glucose oxidase (GOD) onto CuFe-layered double hydroxide (LDH) nanosheets, which exhibited synchronous acid-enhanced/responsive photothermal and chemodynamic synergistic therapy.     

A Supramolecular Photosensitizer System Based on Nano-Cu/ZIF-8 Capped with Water-Soluble Pillar[6]arene and Methylene Blue Host–Guest Complexations

Photodynamic therapy (PDT) as a safe, non-invasive modality for cancer therapy, in which the low oxygen and high glutathione in the tumor microenvironment reduces therapeutic efficiency. In order to overcome these problems, we prepared a supramolecular photosensitive system of O₂-Cu/ZIF-8@ZIF-8@WP6–MB (OCZWM), which was loaded with oxygen to increase the oxygen concentration in the tumor microenvironment, and the Cu²⁺ in the system reacted with glutathione (GSH) to reduce the GSH concentration to generate Cu⁺. It is worth noting that the generated Cu⁺ can produce the Fenton reaction, thus realizing the combination therapy of PDT and chemodynamic therapy (CDT) to achieve the purpose of significantly improving the anti-cancer efficiency.     

One‐Dimensional Fe2P Acts as a Fenton Agent in Response to NIR II Light and Ultrasound for Deep Tumor Synergetic Theranostics

The stringent reaction conditions for an effective Fenton reaction (pH range of 3–4) hinders its application in cancer therapy. Therefore, how to improve the efficiency of the Fenton reaction in a tumor site has been the main obstacle in chemodynamic therapy (CDT). Herein, we report biocompatible one‐dimensional (1D) ferrous phosphide nanorods (FP NRs) with ultrasound (US)‐ and photothermal (PT)‐enhanced Fenton properties and excellent photothermal conversion efficiency (56.6 %) in the NIR II window, showing synergistic therapeutic properties. Additionally, the high photothermal conversion efficiency and excellent traverse relaxivity (277.79 mm ^?1 s^?1) of the FP NRs means they are excellent photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) agents. This is the first report on exploiting the response of metallic phosphides to NIR II laser (1064 nm) and ultrasound to improve the CDT effect with a high therapeutic effect and PA/MR imaging.     

Synthesis of PAMAM-g-PEG-g-DS-g-RB@IO towards dual-modal imaging in atherosclerosis

This study aimed to synthesize a dual-modal magnetic resonance imaging (MRI)/fluorescence imaging (FLI) nanoprobe in order to detect atherosclerosis. Herein, we had prepared the polyamidoamine-graft-poly (ethylene glycol) (PAMAM-g-PEG) as the carrier. Dextran sulfate (DS) and Rhodamine B (RB) were grafted to PAMAM-g-PEG continuously through reductive amination and amidation reaction to synthesize PAMAM-g-PEG-g-DS-g-RB. The structure of PAMAM-g-PEG-g-DS-g-RB was characterized through nuclear magnetic resonance (¹H-NMR) and Fourier transform infrared spectroscopy (FTIR). A new water-soluble superparamagnetic iron oxide nanoparticles (IONPs) has been synthesized through simple ligand exchange between the iron oxide nanaparticles and PAMAM-g-PEG-g-DS-g-RB. The analysis of transmission electron microscopy (TEM) indicated that micelles were well dispersed in water and had uniform sizes. The result of thermogravimetric analysis (TGA) proved that about 83% (mass fraction) polymers were coated on the surface of IONPs. The MRI in vitro evaluation demonstrated a high R2 value (130.8 mM^?1s^?1) to be served as a T2-weighted contrast agent. The cell counting kit (CCK) assay showed no significant toxicity in RAW264.7. The above results confirmed that PAMAM-g-PEG-g-DS-g-RB@IO could play an significant role of MRI and FLI in the atherosclerosis.     

Simultaneous Fenton‐like Ion Delivery and Glutathione Depletion by MnO2‐Based Nanoagent to Enhance Chemodynamic Therapy

Chemodynamic therapy (CDT) utilizes iron‐initiated Fenton chemistry to destroy tumor cells by converting endogenous H₂O₂ into the highly toxic hydroxyl radical (^.OH). There is a paucity of Fenton‐like metal‐based CDT agents. Intracellular glutathione (GSH) with ^.OH scavenging ability greatly reduces CDT efficacy. A self‐reinforcing CDT nanoagent based on MnO₂ is reported that has both Fenton‐like Mn²⁺ delivery and GSH depletion properties. In the presence of HCO₃^?, which is abundant in the physiological medium, Mn²⁺ exerts Fenton‐like activity to generate ^.OH from H₂O₂. Upon uptake of MnO₂‐coated mesoporous silica nanoparticles (MS@MnO₂ NPs) by cancer cells, the MnO₂ shell undergoes a redox reaction with GSH to form glutathione disulfide and Mn²⁺, resulting in GSH depletion‐enhanced CDT. This, together with the GSH‐activated MRI contrast effect and dissociation of MnO₂, allows MS@MnO₂ NPs to achieve MRI‐monitored chemo–chemodynamic combination therapy.     

Tumor microenvironment-responsive MnSiO3-Pt@BSA-Ce6 nanoplatform for synergistic catalysis-enhanced sonodynamic and chemodynamic cancer therapy

Compared with traditional photodynamic therapy （PDT）,ultrasound （US） triggered sonodynamic therapy （SDT） has a wide application prospect in tumor therapy because of its deeper penetration depth.Herein,a novel MnSiO₃-Pt （MP） nanocomposite composed of Mn Si O₃nanosphere and noble metallic Pt was successfully constructed.After modification with bovine serum albumin （BSA） and chlorine e6 （Ce6）,the multifunctional nanoplatform Mn Si O₃-Pt@BSA-Ce6 （MPBC） realized the m...     

In vivo real-time tracking of tumor-specific biocatalysis in cascade nanotheranostics enables synergistic cancer treatment

Glucose oxidase (GOD)-based synergistic cancer therapy has aroused great research interest in the context of cancer treatment due to the inherent biocompatibility and biodegradability. However, this emerging therapeutic system still lacks a strategy to predict and regulate the in vivo biocatalytic behavior of GOD in real time to minimize the side effects on normal tissues. Herein, we developed a tumor-specific cascade nanotheranostic system (BNG) that combines GOD-catalyzed oxidative stress and dual-channel fluorescent sensing, significantly improving the synergistic therapeutic efficacy with real-time feedback information. The nanotheranostic system remains completely silent in the blood circulatory system and selectively releases GOD enzymes in the tumor site, with enhanced near-infrared (NIR) fluorescence at 825 nm. Subsequently, GOD catalyzes H₂O₂ production, triggering cascade reactions with NIR fluorescence at 650 nm as an optical output, along with GSH depletion, enabling synergistic cancer treatment. The designed nanotheranostic system, integrated with tumor-activated cascade reactions and triggering a dual-channel output at each step, represents an insightful paradigm for precise cooperative cancer therapy.

Herein, we described the strategy of cascade nanotheranostics for in real-time tracking of GOD release and thus provide the feedback information of biocatalysis cascade process with significantly enhanced in vivo therapeutic efficiency.      

Synergistic cocatalytic effect of MoO3 and creatinine on Cu–Fenton reactions for efficient decomposition of H2O2

The key scientific problems with conventional Fenton reactions are the acidic pH dependence and low ROS production due to inefficient decomposition of H₂O₂. Although Cu–Fenton reactions can break the pH limitation, there is still an urgent need to improve the overall reaction efficiency, and thus broaden its applicability. Herein, we describe a synergistic strategy by introducing MoO₃ cocatalyst and creatinine (Cr) assistant to enhance the efficiency of Cu–Fenton reactions at near-neutral pH. In this strategy, Cu²⁺ interacts with Cr to form a complex (CuCr₂), which is then mainly linked to MoO₃ via the Cu²⁺ binding site (CuCr₂/MoO₃). Experimental and theoretical calculation results manifest that the CuCr₂/MoO₃ exhibits an excellent cocatalytic activity, which significantly facilitates the rate-limiting step of Cu–Fenton reactions, and enables the efficient decomposition of H₂O₂ for the generation of three reactive oxygen species (ROS, ?OH, ¹O₂, ?O₂^?). More significantly, this cocatalytic system with high oxidation activity can be applied for the detection of Cu²⁺ and ROS-based chemodynamic therapy (CDT), as well as sterilization of Escherichia coli. This study represents a new breakthrough in improving the efficiency of Fenton-based reactions with a facile and promising strategy, and drives great progress in practicality.     

Iron-siRNA Nanohybrids for Enhanced Chemodynamic Therapy via Ferritin Heavy Chain Downregulation

Ferrous iron (Fe²⁺) has more potent hydroxyl radical (⋅OH)-generating ability than other Fenton-type metal ions, making Fe-based nanomaterials attractive for chemodynamic therapy (CDT). However, because Fe²⁺ can be converted by ferritin heavy chain (FHC) to nontoxic ferric form and then sequestered in ferritin, therapeutic outcomes of Fe-mediated CDT agents are still far from satisfactory. Here we report the synthesis of siRNA-embedded Fe⁰ nanoparticles (Fe⁰-siRNA NPs) for self-reinforcing CDT via FHC downregulation. Upon internalization by cancer cells, pH-responsive Fe⁰-siRNA NPs are degraded to release Fe²⁺ and FHC siRNA in acidic endo/lysosomes with the aid of oxygen (O₂). The accompanied O₂ depletion causes an intracellular pH decrease, which further promotes the degradation of Fe⁰-siRNA NPs. In addition to initiating chemodynamic process, Fe²⁺-catalyzed ⋅OH generation facilitates endo/lysosomal escape of siRNA by disrupting the membranes, enabling FHC downregulation-enhanced CDT.     

Degradable nanocatalyst enables antitumor/antibacterial therapy and promotion of wound healing for diabetes via self-enhanced cascading reaction

Diabetic patients often have problems such as residual tumor and wound infection after tumor resection, causing severe clinical problems. It is urgent to develop effective therapies to reach oncotherapy/anti-infection/promotion of wound healing combined treatment. Herein, we propose CS/MnO₂-GOx (CMGOx) nanocatalysts for the specific catalytic generation of ^•OH to inhibit tumors and bacteria in a hyperglycemic environment. The good biocompatible chitosan (CS), as a carrier for the catalyst, exhibits excellent antibacterial effect as well as promotes wound healing. Glucose oxidase (GOx) is loaded on the surface of CS nanoparticles to generate H₂O₂ and gluconic acid by consuming glucose (starvation therapy, ST) and O₂. The MnO₂ depletes glutathione (GSH) to produce Mn²⁺, amplifying oxidative stress and further promoting the activity of Mn²⁺-mediated Fenton-like reaction to produce ^•OH (chemodynamic therapy, CDT) in weak acidic environment. Moreover, the produced gluconic acid lowers the pH of the environment, enhancing chemodynamic therapy (ECDT). The tumor cells and bacteria are efficiently eliminated by the synergistic effect of ST and ECDT. The MnO₂ nanoparticles at neutral environment decomposes H₂O₂ into O₂, which cooperate with CS to promote healing. The self-enhanced cascade reaction of CMGOx in situ exhibits excellent effects of antitumor/antibacterial therapy and promotion of wound healing, offering a promising integrated treatment for diabetic patients after tumor surgical resection.     

Chemodynamic Therapy: Tumour Microenvironment‐Mediated Fenton and Fenton‐like Reactions

Tailored to the specific tumour microenvironment, which involves acidity and the overproduction of hydrogen peroxide, advanced nanotechnology has been introduced to generate the hydroxyl radical (^.OH) primarily for tumour chemodynamic therapy (CDT) through the Fenton and Fenton‐like reactions. Numerous studies have investigated the enhancement of CDT efficiency, primarily the increase in the amount of ^.OH generated. Notably, various strategies based on the Fenton reaction have been employed to enhance ^.OH generation, including nanomaterials selection, modulation of the reaction environment, and external energy fields stimulation, which are discussed systematically in this Minireview. Furthermore, the potential challenges and the methods used to facilitate CDT effectiveness are also presented to support this cutting‐edge research area.     

Tumor Microenvironment Stimuli-Responsive Fluorescence Imaging and Synergistic Cancer Therapy by Carbon-Dot–Cu2+ Nanoassemblies

A method is developed to fabricate tumor microenvironment (TME) stimuli-responsive nanoplatform for fluorescence (FL) imaging and synergistic cancer therapy via assembling photosensitizer (chlorine e6, Ce6) modified carbon dots (CDs-Ce6) and Cu²⁺. The as-obtained nanoassemblies (named Cu/CC nanoparticles, NPs) exhibit quenched FL and photosensitization due to the aggregation of CDs-Ce6. Their FL imaging and photodynamic therapy (PDT) functions are recovered efficiently once they entering tumor sites by the stimulation of TME. Introducing of Cu²⁺ not only provides extra chemodynamic therapy (CDT) function through reaction with hydrogen peroxide (H₂O₂), but also depletes GSH in tumors by a redox reaction, thus amplifying the intracellular oxidative stress and enhancing the efficacy of reactive oxygen species (ROS) based therapy. Cu/CC NPs can act as a FL imaging guided trimodal synergistic cancer treatment agent by photothermal therapy (PTT), PDT, and thermally amplified CDT.     

Facile Fabrication of a Graphene‐based Electrochemical Biosensor for Glucose Detection

A simple and effective glucose biosensor based on immobilization of glucose oxidase (GOD) in graphene (GR)/Nafion film was constructed. The results indicated that the immobilized GOD can maintain its native structure and bioactivity, and the GR/Nafion film provides a favorable microenvironment for GOD immobilization and promotes the direct electron transfer between the electrode substrate and the redox center of GOD. The electrode reaction of the immobilized GOD shows a reversible and surface‐controlled process with the large electron transfer rate constant (k_s) of 3.42±0.08 s^?1. Based on the oxygen consumption during the oxidation process of glucose catalyzed by the immobilized GOD, the as‐prepared GOD/GR/Nafion/GCE electrode exhibits a linear range from 0.5 to 14 mmol·L^?1 with a detection limit of 0.03 mmol·L^?1. Moreover, it displays a good reproducibility and long‐term stability.     

Mo2C‐Derived Polyoxometalate for NIR‐II Photoacoustic Imaging‐Guided Chemodynamic/Photothermal Synergistic Therapy

To overcome the current limitations of chemodynamic therapy (CDT), a Mo₂C‐derived polyoxometalate (POM) is readily synthesized as a new CDT agent. It permits synergistic chemodynamic and photothermal therapy operating in the second near‐infrared (NIR‐II) biological transparent window for deep tissue penetration. POM aggregated in an acidic tumor micro‐environment (TME) whereby enables specific tumor targeting. In addition to the strong ability to produce singlet oxygen (¹O₂) presumably via Russell mechanism, its excellent photothermal conversion enhances the CDT effect, offers additional tumor ablation modality, and permits NIR‐II photoacoustic imaging. Benefitting from the reversible redox property of molybdenum, the theranostics based on POM can escape from the antioxidant defense system. Moreover, combining the specific responsiveness to TME and localized laser irradiation, side‐effects shall be largely avoided.     

Molecularly Imprinted Electrochemical Luminescence Sensor Based on Enzymatic Amplification for Ultratrace Isoproturon Determination

A new molecularly imprinted electrochemical luminescence sensor (MIP‐ECL sensor) was developed for isoproturon (IPU) determination based on the competition reaction between IPU and glucose oxidase labeled IPU (GOD‐IPU). After competition, hydrogen peroxide produced by residual GOD‐IPU on the MIP reacted with luminol to emit electrochemiluminescence (ECL) signal. The ECL intensity decreased when the GOD‐IPU molecules were replaced by IPU molecules in the samples. IPU could be determined in the concentration range from 9×10^?11 mol/L to 5.1×10^?9 mol/L with a detection limit of 3.78×10^?12 mol/L. Water samples were assayed and recoveries ranging from 98.5 % to 102.1 % were obtained.     

Organic Nanoprobes for Fluorescence and 19F Magnetic Resonance Dual‐Modality Imaging

Multimodal imaging techniques have been demonstrated to be greatly advantageous in achieving accurate diagnosis and gained increasing attention in recent decades. Herein, we present a new strategy to integrate the complementary modalities of ¹⁹F magnetic resonance imaging (¹⁹F MRI) and fluorescence imaging (FI) into a polymer nanoprobe composed of hydrophobic fluorescent organic core and hydrophilic fluorinated polymer shell. The alkyne‐terminated fluorinated copolymer (Pn) of 2,2,2‐trifluoroethyl acrylate (TFEA) and poly(ethylene glycol) methyl ether acrylate (PEGA) was first prepared via atom transfer radical polymerization (ATRP). The PEGA plays an important role in both improving ¹⁹F signal and modulating the hydrophilicity of Pn. The alkynyl tail in Pn is readily conjugated with azide modified tetra‐phenylethylene (TPE) through click chemistry to form azo polymer (TPE‐azo‐Pn). The core‐shell nanoprobes (TPE‐P3N) with an average particle size of 57.2 ± 8.8 nm are obtained via self‐assembly with ultrasonication in aqueous solution. These nanoprobes demonstrate high water stability, good biocompatibility, strong fluorescence and good ¹⁹F MRI performance, which present great potentials for simultaneous fluorescence imaging and ¹⁹F–MR imaging.     

Biphenol as an Electron Transfer Mediator for Glucose Oxidase

Abstract

Biphenol (4,4′-dihydroxy-biphenyl) was found to be an electron transfer mediator for glucose oxidase (GOD) of Aspergillus niger. At a glassy carbon electrode, a 1.44×10^-4 M solution of biphenol in phosphate-buffered saline (PBS) at pH 7.4 gives an quasi-reversible, one-electron, pH-sensitive couple at 255mV (relative to the standard calomel electrode). The apparent second-order rate constant for electron transfer from reduced GOD to oxidized biphenol was determined to be 3×10⁵ M^-1 s^-1. When biphenol and GOD are cophysiadsorbed on a graphite electrode immersed in PBS and held at 400mV, a glucose-dependent current response is noted. In addition to the predominant quasi-reversible biphenol redox couple, repetitive cyclic voltammetry at a graphite electrode gave rise to a polybiphenol polymer; this is most marked at a pH above the biphenol pK_a of about 9.5. At pH 7.4, the polymerization is less significant. Polybiphenol formed either side of the pK_a remains electrochemically active (E°_app. = 245mV) but no longer mediates GOD.     

A Multifunctional Biomaterial with NIR Long Persistent Phosphorescence,Photothermal Response and Magnetism

There are many reports on long persistent phosphors (LPPs) applied in bioimaging. However, there are few reports on LPPs applied in photothermal therapy (PTT), and an integrated system with multiple functions of diagnosis and therapy. In this work, we fabricate effective multifunctional phosphors Zn₃Ga₂SnO₈: Cr³⁺, Nd³⁺, Gd³⁺ with NIR persistent phosphorescence, photothermal response and magnetism. Such featured materials can act as NIR optical biolabels and magnetic resonance imaging (MRI) contrast agents for tracking the early cancer cells, but also as photothermal therapeutic agent for killing the cancer cells. This new multifunctional biomaterial is expected to open a new possibility of setting up an advanced imaging‐guided therapy system featuring a high resolution for bioimaging and low side effects for the photothermal ablation of tumors.