Nanocatalytic Therapy Research Articles

Bimetallic oxide nanozyme-mediated depletion of glutathione to boost oxidative stress for combined nanocatalytic therapy

Although nanocatalytic therapy has become an emerging strategy for tumor treatment, the therapeutic effects of reactive oxygen species (ROS)-mediated treatment are still seriously limited by the inherent flaws of the enzymatic activities and the specific physicochemical properties of the tumor microenvironment (TME). Herein, we report an ultrasmall bimetallic oxide nanozyme (CuFe2O4@PEG, CFOs) for programmable multienzyme-like activities-primed combined therapy. Under the acidic condition, abundant highly toxic ROS can be generated through the peroxidase activity of CFOs with overexpressed hydrogen peroxide (H2O2) in the tumor. High metal ion utilization of bimetallic oxide nanozymes is related to the size effect and topological structure. Furthermore, glutathione peroxidase activity-initiated depletion of GSH disrupts the intracellular antioxidant defense system and further amplifies the oxidative stress in turn. Subsequently, oxygen generation originating from the catalase activity of CFOs relieves tumor hypoxia and achieves exceptional TME-customized therapeutic effects. Notably, the high photothermal effect (η = 41.12%) of CFOs in the second near-infrared biological windows leads to the combinational inhibition of tumor growth. In summary, this report provides a paradigm for the rational design of TME-responsive and ROS-mediated nanocatalytic treatment, which is promising for achieving superior therapeutic efficiency.

Phase-change cascaded nanomedicine for intensive photothermal-enhanced nanocatalytic therapy via tumor oxidative stress amplification

Insufficient concentrations of intracellular substrates such as hypoxia and H 2 O 2 considerably reduce the effectiveness of reactive oxygen species (ROS)-associated cancer therapy. Modulating the tumor microenvironment (TME) for augmenting efficacy has become a promising strategy. Herein, a phase-change cascaded nanomedicine (Lap-IrO x @PCM) was constructed via co-encapsulation of iridium oxide nanozyme (IrO x ) and β-lapachone (Lap) by using thermal-responsive phase-change materials (PCMs). After photothermal activation, the protective PCM layer was melted, causing the rapid release of IrO x and Lap. Simultaneously, the peroxidase-like nanozyme IrO x reacted with endogenous H 2 O 2 to liberate highly toxic hydroxyl radicals (•OH) for inducing tumor cell death. Meanwhile, IrO x as another glutathione peroxidase nanozyme also consumed glutathione (GSH) to protect ROS from scavenging. Importantly, the released Lap efficiently generated H 2 O 2 for facilitating the catalytic efficacy of IrO x and provoke the cleavage of heat shock protein 90 (Hsp90) for overcoming tumor heat tolerance in photothermal therapy (PTT). As systematically demonstrated both in vitro and in vivo , this well-defined system achieved a superior antitumor effect via mild photothermal-enhanced nanocatalytic therapy. Our findings have provided the proof of concept of the phase change-mediated, in vivo catalytic activity of nanozymes that can be customized for intensive, TME-mediated, self-enhanced nanocatalytic cancer therapy. We report a domino-like nanomedicine (Lap-IrO x @PCM) that possesses both H 2 O 2 self-supply and GSH-elimination properties for achieving highly cascaded catalytic-therapeutic outcomes by integrating a peroxidase-like moiety of the IrO x nanozyme and β-Lapachone within a thermal-responsive phase-change material (PCM). This work presents a universal idea of a phase-change nanomedicine design for intensive, mild PTT-enhanced nanocatalytic therapy. • A concept of “phase change nanomedicine-mediated H 2 O 2 self-supplying” strategy is proposed. • β-Lapachone is exploited as a H 2 O 2 productor and heat shock protein inhibitor to fabricate cascade nanocatalyst. • The engineered Lap-IrO x @PCM presents an idea of a phase-change nanomedicine design for intensive nanocatalytic therapy. • This work provides the first example of a nanozyme-type phase-change nanomedicine.

A ROS-Sensitive Nanozyme-Augmented Photoacoustic Nanoprobe for Early Diagnosis and Therapy of Acute Liver Failure.

Early diagnosis of acute liver failure (ALF) is critical for curable treatment of patients, because most existing ALF therapies have narrow therapeutic time windows after disease onset. Reactive oxygen species (ROS), which lead to the sequential occurrences of hepatocyte necrosis and the leakage of alanine aminotransferase (ALT), represent early biomarkers of ALF. Photoacoustic imaging is emerging as a powerful tool for in vivo imaging of ROS. However, high-performance imaging probes that can boost the photoacoustic signals of the short-lived ROS of ALF are yet to be developed, and there remains a great challenge for ROS-based imaging of ALF. Herein, a ROS-sensitive nanozyme-augmented photoacoustic nanoprobe for successful in vivo imaging of ALF is presented. The deep-penetrating photoacoustic signals of the nanoprobe can be activated by the overexpressed ROS in ALF due to the synergy between nanocatalytic bubbles generation and thermoelastic expansion. Impressively, the nanozyme-augmented ROS imaging enables earlier diagnosis of ALF than the clinical ALT method, and the ROS-activated catalytic activity of nanoprobe permits timely nanocatalytic therapy of ALF.

Facile fabrication of a biodegradable multi-hollow iron phosphate nanoplatform for tumor-specific nanocatalytic therapy and chemotherapy.

In this study, a type of biodegradable multi-hollow iron phosphate (FeP) with excellent Fenton reaction ability and doxorubicin (DOX) loading capacity is synthesized in one-pot. This hollow FeP with complex interior not only affords high drug loading efficiency, but also obviates DOX leakage in normal tissues. In order to inhibit the formation of inert Fe(OH)x and endow the nanoplatform with a highly hydrophilic surface, PEG was anchored to it with a dopamine linkage, which formed an Fe chelating complex. DOX-loaded FeP modified with PEG could be disintegrated when responding to the lysosomal acid environment, releasing both ferric and ferrous ions as well as DOX. Therefore, apart from chemotherapy with DOX, the continuously generated iron ions catalyze a fast Fenton reaction with the innate H2O2 in tumor cells and produce abundant highly toxic hydroxyl radicals for nanocatalytic tumor therapy. Taken together, we believe that this nanoplatform will significantly advance the fields of both Fe-based nanomaterials and nanocatalytic tumor therapy.

PH-Responsive Au@Pd bimetallic core-shell nanorods for enhanced synergistic targeted photothermal-augmented nanocatalytic therapy in the second near-infrared window.

Nanotheranostic agents based on plasmonic nanostructures with their resonance wavelengths located in the second near-infrared window (NIR-II) have gained significant attention in profound tumor photothermal therapy. However, the modulation of localized surface plasmon resonance of gold nanomaterials from the first near-infrared (NIR-I) window to the NIR-II window is still challenging. The structures and compositions of the plasmonic nanomaterials have demonstrated promising characteristics in controlling the optical properties of plasmonic nanostructures. Here, gold nanorod (Au NR) coated with an ultrathin palladium (Pd) shell was developed for tumor-targeted NIR-II photothermal-augmented nanocatalytic therapy through the combination of compositional manipulation and structural evolution strategies. These Au@Pd core-shell hybrid NRs (HNRs) were functionalized with biocompatible chitosan (CS) to acquire lower toxicity and higher stability in physiological systems. Further, Au@Pd-CS HNRs were endowed with an excellent targeting ability by conjugating with folic acid (FA). The as-synthesized Au@Pd-CS-FA HNRs show efficient and complete photothermal ablation of tumor cells upon 1064 nm laser irradiation. The remarkable photothermal conversion efficiency of 69.0% was achieved, which is superior to many reported photothermal agents activated in the NIR-II region. Excitingly, Au@Pd-CS-FA HNRs have peroxidase and catalase activities, simultaneously producing ˙OH for catalytic therapy and O2 for relieving tumor hypoxia and photodynamic therapy. Additionally, in vivo tumor photothermal therapy was carried out, where the biocompatible Au@Pd-CS-FA HNRs penetrate intensely into the tumor cells and consequently show remarkable therapeutic effects. The idea about plasmonic modulation behind the bimetallic core-shell nanostructure in this report can be extended to construct new classes of metal-based nanotheranostic agents with dual-modal combined therapy as an alternative to traditional chemotherapy.

Dual-imaging magnetic nanocatalysis based on Fenton-like reaction for tumor therapy.

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 Fe3O4 nanoparticles have been integrated into poly(lactic-co-glycolic acid) (PLGA) to fabricate a sequential nanocatalyst (designated as GOx@PLGA-Fe3O4). 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-Fe3O4 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.

Dual enzyme-mimic nanozyme based on single-atom construction strategy for photothermal-augmented nanocatalytic therapy in the second near-infrared biowindow

Nanozyme-based catalytic therapy, an emerging therapeutic pattern, has significantly incorporated in the advancement of tumor therapy by generating lethal reactive oxygen species. Nevertheless, most of the nanozymes have mono catalytic performances with H2O2 in the tumor microenvironment (TME), which lowers their therapeutic efficiency. Herein, we design a newly-developed single-atom Fe dispersed N-doped mesoporous carbon nanospheres (SAFe-NMCNs) nanozyme with high H2O2 affinity for photothermal-augmented nanocatalytic therapy. The SAFe-NMCNs nanozyme possesses dual enzyme-mimic catalytic activity which not only acts as a catalase-mimic role to achieve ultrasonic imaging in tumor site by O2 generation, but also exhibits the superior peroxidase-mimic catalytic performance to generate •OH for nanocatalytic therapy. Besides, the SAFe-NMCNs nanozyme with strong optical absorption in the second near-infrared (NIR-II) region shows excellent photothermal conversion performance. The peroxidase-mimic catalytic process of SAFe-NMCNs nanozyme is realized using density functional theory (DFT). Both in vitro and in vivo results indicate that the SAFe-NMCNs nanozyme can efficiently suppress tumor cells growth by a synergistic therapy effect with photothermal-augmented nanocatalytic therapy. The work developed a single-atom-coordinated nanozyme with dual-enzyme catalytic performance and achieve hyperthermia-augmented nanocatalytic therapy effect, can open a window for potential biological applications.

Fe3 O4 /Ag/Bi2 MoO6 Photoactivatable Nanozyme for Self-Replenishing and Sustainable Cascaded Nanocatalytic Cancer Therapy.

Catalytic cancer therapy based on nanozymes has recently attracted much interest. However, the types of the current nanozymes are limited and their efficiency is usually compromised and not sustainable in the tumor microenvironment (TME). Therefore, combination therapy involving additional therapeutics is often necessary and the resulting complication may jeopardize the practical feasibility. Herein, an unprecedented "all-in-one" Fe3 O4 /Ag/Bi2 MoO6 nanoparticle (FAB NP) is rationally devised to achieve synergistic chemodynamic, photodynamic, photothermal therapy with guidance by magnetic resonance, photoacoustic, and photothermal imaging. Based on its manifold nanozyme activities (mimicking peroxidase, catalase, superoxide dismutase, glutathione oxidase) and photodynamic property, cascaded nanocatalytic reactions are enabled and sustained in TME for outstanding therapeutic outcomes. The working mechanisms underlying the intraparticulate interactions, sustainability, and self-replenishment arising from the coupling between the nanocatalytic reactions and nanozyme activities are carefully revealed, providing new insights into the design of novel nanozymes for nanocatalytic therapy with high efficiency, good specificity, and low side effects.

Ultrasound‐Augmented Nanocatalytic Ferroptosis Reverses Chemotherapeutic Resistance and Induces Synergistic Tumor Nanotherapy

AbstractInducing ferroptosis has been acknowledged as an emerging strategy to kill drug‐resistant tumor cells, but how to efficiently induce ferroptosis at the tumor site and enhance its therapeutic efficacy are still highly challenging. In this work, an ultrasound (US)‐augmented nanocatalytic ferroptosis strategy is implemented by a GA‐Fe(II)‐based liposomal nanosystem, which simultaneously encapsulates doxorubicin hydrochloride (DOX), for reversing chemotherapeutic resistance and inducing synergistic ferroptosis/apoptosis‐based nanotherapy. GA‐Fe(II), as an iron‐containing Fenton catalyst that catalyzes the persistent conversion of H2O2 to hydroxyl radicals, is utilized to deplete glutathione and deliver excess iron into cells for accumulating lipid peroxidation and inducing ferroptosis in DOX‐resistant MCF‐7/ADR cancer cells. US irradiation is capable of promoting cell phagocytosis of nano‐agents, enhancing Fenton reaction, and controlling drug release at tumor sites to strengthen nanocatalytic therapy. Transcriptomics analysis reveals that the US‐augmented Fenton reaction enables the down‐regulation of PGC‐1α and Bcl‐2 expression, rendering MCF‐7/ADR cells susceptible to DOX‐induced apoptosis. The distinct US‐responsive Fenton reaction collaborating with chemotherapy substantially reverses tumor drug resistance and achieves high tumor‐killing efficacy in MCF‐7/ADR cells and MCF‐7/ADR tumor‐bearing mice, suggesting that such a synergistic ferroptosis/apoptosis‐targeting strategy is instructive to the future design of therapeutic regimens against drug‐resistant tumors.

Multifunctional cascade nanocatalysts for NIR-II-synergized photonic hyperthermia-strengthened nanocatalytic therapy of epithelial and embryonal tumors

Chemodynamic therapy, which produces cytotoxic hydroxyl radicals through intratumoral Fenton reactions, has been extensively explored in nanomedicine for cancer treatment. However, the limited endogenous hydrogen peroxide (H2O2) levels, which serve as the reactant, weakens the anticancer effect of the Fenton reaction. In this work, a cascade catalytically reactive nanosystem has been constructed for the treatment of epithelial and embryonal tumors with high synergetic efficacy through the integration of natural glucose oxidase (GOD) and polyethylene glycol (PEG) onto the surface of Fe3S4 nanoplates (abbreviated as Fe3S4-PEG-GOD NPs). The GOD component consumes glucose in tumor and produces a large amount of H2O2, which provides rich substrates for the Fenton reaction catalyzed by the Fe catalytic center of the nanoplates. The intriguing photothermal conversion efficiency (45%) of the constructed composite nanocatalysts in the second near infrared (NIR-II) biowindow allows for photothermal treatment to substantially strengthen and synergize the anticancer effects of nanocatalysts both in vitro and in vivo. This synergy occurs through generation of a hyperthermic effect necessary for promoting the sequential catalytic reaction. The synergistic anticancer effect has been verified in both epithelial and embryonal tumor mouse models, and provides justification for the biomedical use of multifunctional nanocatalysts for versatile tumor nanotherapeutics.

Extracellular-vesicles delivered tumor-specific sequential nanocatalysts can be used for MRI-informed nanocatalytic Therapy of hepatocellular carcinoma.

Background: Conventional therapeutic strategies for advanced hepatocellular carcinoma (HCC) remains a great challenge, therefore the alternative therapeutic modality for specific and efficient HCC suppression is urgently needed.Methods: In this work, HCC-derived extracellular vesicles (EVs) were applied as surface nanocarrier for sequential nanocatalysts GOD-ESIONs@EVs (GE@EVs) of tumor-specific and cascade nanocatalytic therapy against HCC. By enhancing the intracellular endocytosis through arginine-glycine-aspartic acid (RGD)-targeting effect and membrane fusion, sequential nanocatalysts led to more efficient treatment in the HCC tumor region in a shorter period of time.Results: Through glucose consumption as catalyzed by the loaded glucose oxidase (GOD) to overproduce hydrogen peroxide (H2O2), highly toxic hydroxyl radicals were generated by Fenton-like reaction as catalyzed by ESIONs, which was achieved under the mildly acidic tumor microenvironment, enabling the stimuli of the apoptosis and necrosis of HCC cells. This strategy demonstrated the high active-targeting capability of GE@EVs into HCC, achieving highly efficient tumor suppression both in vitro and in vivo. In addition, the as-synthesized nanoreactor could act as a desirable nanoscale contrast agent for magnetic resonance imaging, which exhibited desirable imaging capability during the sequential nanocatalytic treatment.Conclusion: This application of surface-engineering EVs not only proves the high-performance catalytic therapeutic modality of GE@EVs for HCC, but also broadens the versatile bio-applications of EVs.

A polydopamine-gated biodegradable cascade nanoreactor for pH-triggered and photothermal-enhanced tumor-specific nanocatalytic therapy.

Despite the great potential of cascade catalytic reactions in tumor treatment, uncontrolled catalytic activities in vivo lead to inevitable off-target toxicity to normal tissues, which greatly hampers their clinical conversion. Herein, an intelligent cascade nanoreactor (hMnO2-Au@PDA, hMAP) was constructed by depositing glucose oxidase (GOx)-mimicking ultrasmall gold nanoparticles (Au NPs) into honeycomb-shaped manganese oxide (hMnO2) nanostructures and then coating them with polydopamine (PDA) to achieve pH-responsive and photothermal-enhanced nanocatalytic therapy. Upon exposure to the mild acidic tumor microenvironment (TME), the PDA gatekeeper would collapse, and the inner hMnO2 could simultaneously deplete glutathione (GSH) and generate Mn2+, while a considerable amount of H2O2 produced from the oxidation of glucose by GOx-mimicking Au NPs could accelerate the Mn2+-mediated Fenton-like reaction, yielding sufficient highly toxic ˙OH. More importantly, the pH-responsive cascade reaction between Au NPs and hMnO2 could be further enhanced by localized hyperthermia induced from PDA under near-infrared (NIR) laser irradiation, thereby inducing significant cell apoptosis in vitro and tumor inhibition in vivo. This work provided a promising paradigm by innovatively designing a TME-responsive and photothermal-enhanced cascade catalytic nanoreactor for safe and efficient cancer therapy.

Facile engineering of silk fibroin capped AuPt bimetallic nanozyme responsive to tumor microenvironmental factors for enhanced nanocatalytic therapy.

Background: Reactive oxygen species (ROS), as a category of highly reactive molecules, are attractive for eliminating tumor cells in situ. However, the intrinsic tumor microenvironment (TME) always compromises treatment efficacy. In another aspect, silk fibroin (SF), as a category of natural biomacromolecules, is highly promising for synthesis of metallic nanocrystals via biomineralization.Methods: As a proof-of-concept study, AuPt bimetallic nanozyme derived from bioinspired crystallization of chloroauric acid and chloroplatinic acid was facilely developed in the presence of silk fibroin (SF). Antitumor effects caused by the as-synthesized AuPt@SF (APS) nanozyme were demonstrated in 4T1 tumor cells in vitro and xenograft tumor models in vivo.Results: APS nanozyme can decompose glucose to constantly supply H2O2 and deplete intracellular glutathione (GSH). APS nanozyme can simultaneously convert adsorbed O2 and endogenic H2O2 into superoxide radicals (•O2-) and hydroxyl radical (•OH), respectively, upon highly efficient catalytic reaction. Subsequently, these cytotoxic ROS cause irreversible damage to the cell membrane, nucleic acid and mitochondria of tumors. Upon fluorescence/photoacoustic (FL/PA)-imaging guidance, remarkable tumor damage based on the current nanoplatform was confirmed in vivo.Conclusion: The objective of our investigation is to supply more useful insights on the development of SF-based nanocatalysts, which are specifically responsive to TME for extremely efficient tumor theranostics.

Nanocatalytic Medicine of Iron-Based Nanocatalysts

Iron can be found in all mammalian cells and is of critical significance to diverse cellular activities within human bodies. Widespread applications and the underlying chemical and biological funda...

Tumor-responsive copper-activated disulfiram for synergetic nanocatalytic tumor therapy

Exploring alternative biomedical use of traditional drugs in different disease models is highly important as it can reduce the cost of drug development and overcome several critical issues of traditional chemodrugs such as low chemotherapeutic efficiency, severe side effect, and drug resistance. Disulfiram (DSF), a clinically approved alcohol-aversion drug, was recently demonstrated to feature tumor-growth suppression effect along with the co-administration of Cu2+ species, but direct Cu2+ administration mode might cause severe toxicity originating from low Cu2+ accumulation into the tumor and nonspecific Cu2+ distribution-induced cytotoxicity. Based on the intriguing drug-delivery performance of nanoscale metal-organic frameworks (MOFs), we herein construct HKUST nMOFs as the Cu2+ self-supplying nanocarriers for efficient delivery of the DSF drug. The mildly acidic condition of tumor microenvironment initially triggered the release of Cu ions from HKUST nMOFs, which further reacted with the encapsulated DSF to form toxic Cu(DDTC)2 (activation) for tumor chemotherapy. Especially, during the Cu(DDTC)2 complexation, Cu+ species were formed concomitantly, triggering the intratumoral nanocatalytic therapy for the generation of reactive oxygen species to synergistically destroying the tumor cells/tissue. As a result, synergetic tumor-responsive chemotherapy and nanocatalytic therapy are enabled by DSF@HKUST nanodrugs, as demonstrated by the dominant anticancer efficacy with satisfied biocompatibility both in vitro and in vivo. The present work offers a sophisticated strategy for tumor-responsive nontoxic-to-toxic therapeutic with high biocompatibility.

GSH-Depleted Nanozymes with Hyperthermia-Enhanced Dual Enzyme-Mimic Activities for Tumor Nanocatalytic Therapy.

Nanocatalytic therapy, using artificial nanoscale enzyme mimics (nanozymes), is an emerging technology for therapeutic treatment of various malignant tumors. However, the relatively deficient catalytic activity of nanozymes in the tumor microenvironment (TME) restrains their biomedical applications. Here, a versatile and bacteria-like PEG/Ce-Bi@DMSN nanozyme is developed by coating uniform Bi2 S3 nanorods (NRs) with dendritic mesoporous silica (Bi2 S3 @DMSN) and then decorating ultrasmall ceria nanozymes into the large mesopores of Bi2 S3 @DMSN. The nanozymes exhibit dual enzyme-mimic catalytic activities (peroxidase-mimic and catalase-mimic) under acidic conditions that can regulate the TME, that is, simultaneously elevate oxidative stress and relieve hypoxia. In addition, the nanozymes can effectively consume the overexpressed glutathione (GSH) through redox reaction. Photothermal therapy (PTT) is introduced to synergistically improve the dual enzyme-mimicking catalytic activities and depletion of the overexpressed GSH in the tumors by photonic hyperthermia. This is achieved by taking advantage of the desirable light absorbance in the second near-infrared (NIR-II) window of the PEG/Ce-Bi@DMSN nanozymes. Subsequently the reactive oxygen species (ROS)-mediated therapeutic efficiency is significantly improved. Therefore, this study provides a proof of concept of hyperthermia-augmented multi-enzymatic activities of nanozymes for tumor ablation.

Chemistry of Advanced Nanomedicines in Cancer Cell Metabolism Regulation.

Tumors reprogram their metabolic pathways to meet the bioenergetic and biosynthetic demands of cancer cells. These reprogrammed activities are now recognized as the hallmarks of cancer, which not only provide cancer cells with unrestricted proliferative and metastatic potentials, but also strengthen their resistance against stress conditions and therapeutic challenges. Although recent progress in nanomedicine has largely promoted the developments of various therapeutic modalities, such as photodynamic therapy, photothermal therapy, nanocatalytic therapy, tumor‐starving/suffocating therapy, etc., the therapeutic efficacies of nanomedicines are still not high enough to achieve satisfactory tumor‐suppressing effects. Therefore, researchers are obliged to look back to the essence of cancer cell biology, such as metabolism, for tailoring a proper therapeutic regimen. In this work, the characteristic metabolic pathways of cancer cells, such as aerobic respiration, glycolysis, autophagy, glutaminolysis, etc. are reviewed, to summarize the very recent advances in the smart design of nanomedicines that can regulate tumor metabolism for enhancing conventional therapeutic modalities. The underlying chemistry of these nanomedicines by which tumor metabolism is harnessed, is also discussed in a comprehensive manner. It is expected that by harnessing tumor metabolism cancer nanotherapeutics will be substantially improved in the future.

Wonton-like nanoparticles with dual enzyme-mimetic function for the multiple-imaging-guided cancer combined therapy

The significant role of some natural enzymes in tumor therapy is recently widely explored due to their catalyzing specific endogenous substrates in tumor part. However, the catalytic activity of these natural enzymes differs in various and complex tumor microenvironment, which eventually is difficult to be guaranteed. To address this issue, a new wonton-like Bi@PVP@AuPt nanoparticle with both glucose oxidase- and peroxidase-like enzyme function were designed to replace natural enzymes for nanocatalytic therapy. Bi@PVP@AuPt nanoparticles can accumulate in tumor sites and degrade endogenous glucose and hydrogen peroxide, to produce cytotoxic reactive oxygen species in tumor cells, while the loose structure of the wonton-like shape allows for better contact between the substrate and the nanoparticles. At the same time, the Bi@PVP@AuPt nanoparticles can be stimulated by near-infrared laser, leading to the hyperthermia-inducing apoptosis of tumor. Moreover, Bi@PVP@AuPt nanoparticles also showed favorable imaging effects of X-ray computed tomography, photoacoustic, and infrared thermal imaging, which can also assist clinical diagnosis and precise treatment.

Photothermal-reinforced and glutathione-triggered in Situ cascaded nanocatalytic therapy

Tumor microenvironment (TME)-responsive nanoformulations that catalyze a cascade of intracellular redox reactions showed promise for tumor treatment with high specificity and efficiency. In this study, we report Cu2+-doped zeolitic imidazolate frameworks-coated polydopamine nanoparticles (PDA@Cu/ZIF-8 NPs) for glutathione-triggered and photothermal-reinforced sequential catalytic therapy against breast cancer. In the TME, the PDA@Cu/ZIF-8 NPs could initially react with antioxidant glutathione (GSH), inducing GSH depletion and Cu+ generation. Whereafter, the generated Cu+ would catalyze local H2O2 to produce highly toxic hydroxyl radicals (·OH) through an efficient Fenton-like reaction even in weakly acidity. Importantly, the PDA could exert excellent photothermal conversion effect to simultaneously accelerate GSH consumption and improve the Fenton-like reaction for further expanding the intracellular oxidative stress, which innovatively achieves a synergistic photothermal-chemodynamic therapy for highly efficient anticancer treatment.

A Metal-Organic Framework (MOF) Fenton Nanoagent-Enabled Nanocatalytic Cancer Therapy in Synergy with Autophagy Inhibition.

Nanocatalytic medicine has been developed recently to trigger intratumoral generation of highly toxic reactive oxygen species (ROS) for cancer therapy, which, unfortunately, suffers from compromised therapeutic efficacy due to a self-protective mechanism, autophagy, of cancer cells to mitigate oxidative damage. In this work, during the efforts of ROS generation by nanocatalytic medicine, a pharmacological autophagy inhibition strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. An iron-containing metal-organic framework [MOF(Fe)] nanocatalyst as a peroxidase mimic is used to catalyze the generation of highly oxidizing •OH radicals specifically within cancer cells, while chloroquine is applied to deacidify lysosomes and inhibit autophagy, cutting off the self-protection pathway under severe oxidative stress. Cancer cells fail to extract their components to detoxicate and strengthen themselves, finally succumbing to the ROS-induced oxidative damage during nanocatalytic therapy. Both in vitro and in vivo results demonstrate the synergy between nanocatalytic therapy and autophagy inhibition, suggesting that such a combined strategy is applicable to amplify tumor-specific oxidative damage and may be informative to future design of therapeutic regimen.