Nanocatalytic Medicine Research Articles

Hyperthermia-triggered NO release based on Cu-doped polypyrrole for synergistic catalytic/gas cancer therapy

Nitric oxide (NO) is a crucial gaseous medium for tumor growth and progression, but it may also cause mitochondrial disorder and DNA damage by drastically increasing its concentration in tumor. Due to its challenging administration and unpredictable release, NO based gas therapy is difficult to eliminate malignant tumor at low safe doses. To address these issues, herein, we develop a multifunctional nanocatalyst called Cu-doped polypyrrole (CuP) as an intelligent nanoplatform (CuP-B@P) to deliver the NO precursor BNN6 and specifically release NO in tumors. Under the aberrant metabolic environment of tumors, CuP-B@P catalyzes the conversion of antioxidant GSH into GSSG and excess H2O2 into ·OH through Cu+/Cu2+ cycle, which results in oxidative damage to tumor cells and the concomitant release of cargo BNN6. More importantly, after laser exposure, nanocatalyst CuP can absorb and convert photons into hyperthermia, which in turn, accelerates the aforesaid catalytic efficiency and pyrolyzes BNN6 into NO. Under the synergistic effect of hyperthermia, oxidative damage, and NO burst, almost complete tumor elimination is achieved in vivo with negligible toxicity to body. Such an ingenious combination of NO prodrug and nanocatalytic medicine provides a new insight into the development of NO based therapeutic strategies. Statement of significanceA hyperthermia-responsive NO delivery nanoplatform (CuP-B@P) based on Cu-doped polypyrrole was designed and fabricated, in which CuP catalyzed the conversion of H2O2 and GSH into ·OH and GSSG to induce intratumoral oxidative damage. After laser irradiation, hyperthermia ablation and responsive release of NO further coupled with oxidative damage to eliminate malignant tumors. This versatile nanoplatform provides new insights into the combined application of catalytic medicine and gas therapy.

Schottky Junction Nanozyme Based on Mn-Bridged Co-Phthalocyanines and Ti3C2Tx Nanosheets Boosts Integrative Type I and II Photosensitization for Multimodal Cancer Therapy.

Cancer phototheranostics have the potential for significantly improving the therapeutic effectiveness, as it can accurately diagnose and treat cancer. However, the current phototheranostic platforms leave much to be desired and are often limited by tumor hypoxia. Herein, a Schottky junction nanozyme has been established between a manganese-bridged cobalt-phthalocyanines complex and Ti3C2Tx MXene nanosheets (CoPc-Mn/Ti3C2Tx), which can serve as an integrative type I and II photosensitizer for enhancing cancer therapeutic efficacy via a photoacoustic imaging-guided multimodal chemodynamic/photothermal/photodynamic therapy strategy under near-infrared (808 nm) light irradiation. The Schottky junction not only possessed a narrow-bandgap, enhanced electron-hole separation ability and exhibited a potent redox potential but also enabled improved H2O2 and O2 supplying performances in vitro. Accordingly, the AS1411 aptamer-immobilized CoPc-Mn/Ti3C2Tx nanozyme illustrated high accuracy and excellent anticancer efficiency through a multimodal therapy strategy in in vitro and in vivo experiments. This work presents a valuable method for designing and constructing a multifunctional nanocatalytic medicine platform for synergistic cancer therapy of solid tumors.

Self-Propelled Janus Nanocatalytic Robots Guided by Magnetic Resonance Imaging for Enhanced Tumor Penetration and Therapy

Biomedical micro/nanorobots as active delivery systems with the features of self-propulsion and controllable navigation have made tremendous progress in disease therapy and diagnosis, detection, and biodetoxification. However, existing micro/nanorobots are still suffering from complex drug loading, physiological drug stability, and uncontrollable drug release. To solve these problems, micro/nanorobots and nanocatalytic medicine as two independent research fields were integrated in this study to achieve self-propulsion-induced deeper tumor penetration and catalytic reaction-initiated tumor therapy in vivo. We presented self-propelled Janus nanocatalytic robots (JNCRs) guided by magnetic resonance imaging (MRI) for in vivo enhanced tumor therapy. These JNCRs exhibited active movement in H2O2 solution, and their migration in the tumor tissue could be tracked by non-invasive MRI in real time. Both increased temperature and reactive oxygen species production were induced by near-infrared light irradiation and iron-mediated Fenton reaction, showing great potential for tumor photothermal and chemodynamic therapy. In comparison with passive nanoparticles, these self-propelled JNCRs enabled deeper tumor penetration and enhanced tumor therapy after intratumoral injection. Importantly, these robots with biocompatible components and byproducts exhibited biosecurity in the mouse model. It is expected that our work could promote the combination of micro/nanorobots and nanocatalytic medicine, resulting in improved tumor therapy and potential clinical transformations.

Nitrogen-doped carbon nanodots deposited on titania nanoparticles: Unconventional near-infrared active photocatalysts for cancer therapy

Cancer represents a major public health issue and a primary cause of death for the mankind and the search for alternative cancer treatments that assist or alleviate the drawbacks of current cancer therapies remains imperative. Nanocatalytic medicine represents a new discipline that aims at exploiting the unique response of heterogeneous catalysts exposed to unconventional conditions such as those encountered in the tumor microenvironment (TME). Photo-triggered cancer therapies using light-activable catalytic materiales can stimulate and activate multiple biological processes and represent a very promising field of study. Herein, we evaluate the use of carbon nanodots with different composition (CNDs) retrieved by laser pyrolysis as potential near-infrared (NIR) photosensitizers able to activate P25 semiconductor nanostructured photocatalysts. We describe the enhanced photocatalytic response towards glucose conversion and reactive oxygen species (ROS) generation upon irradiation with NIR-LEDs when CNDs doped with heteroatoms were tested. The most active photocatalysts were evaluated in the presence of cancer cells and revealed a promising photodynamic effect under NIR irradiation. This work represents one of the scarce examples of a conventional inorganic photocatalyst containing TiO2 that is translated into a biomedical application with a successful outcome.

Copper Single-Atom Jellyfish-like Nanomotors for Enhanced Tumor Penetration and Nanocatalytic Therapy

Single-atom catalysts with extraordinary catalytic activity have been receiving great attention in tumor therapy. However, most single-atom catalysts lack self-propulsion properties, restricting them from actively approaching cancer cells or penetrating the interior of tumors. Herein, we design N-doped jellyfish-like mesoporous carbon nanomotors coordinated with single-atom copper (Cu-JMCNs). It is a combination of single-atom nanocatalytic medicine and nanomotor self-propulsion for cancer therapy. The Cu single atom can catalyze H2O2 into toxic hydroxyl radical (•OH) for chemodynamic therapy (CDT). Near-infrared light triggers Cu-JMCNs to achieve self-thermophoretic motion because of the jellyfish-like asymmetric structure and photothermal property of carbon, which significantly improves the cellular uptake and the penetration of three-dimensional tumors. In vivo experiments indicate that the combination of single-atom Cu for CDT and near-infrared light propulsion can achieve over 85% tumor inhibition rate. This work sheds light on the development of advanced nanomotors with single-atom catalysts for biomedical applications.

MnOOH-Catalyzed Autoxidation of Glutathione for Reactive Oxygen Species Production and Nanocatalytic Tumor Innate Immunotherapy.

The antioxidant system, signed with reduced glutathione (GSH) overexpression, is the key weapon for tumor to resist the attack by reactive oxygen species (ROS). Counteracting the ROS depletion by GSH is an effective strategy to guarantee the antitumor efficacy of nanocatalytic therapy. However, simply reducing the concentration of GSH does not sufficiently improve tumor response to nanocatalytic therapy intervention. Herein, a well-dispersed MnOOH nanocatalyst is developed to catalyze GSH autoxidation and peroxidase-like reaction concurrently and respectively to promote GSH depletion and H2O2 decomposition to produce abundant ROS such as hydroxyl radical (·OH), thereby generating a highly effective superadditive catalytic therapeutic efficacy. Such a therapeutic strategy that transforms endogenous "antioxidant" into "oxidant" may open a new avenue for the development of antitumor nanocatalytic medicine. Moreover, the released Mn2+ can activate and sensitize the cGAS-STING pathway to the damaged intratumoral DNA double-strands induced by the produced ROS to further promote macrophage maturation and M1-polarization, which will boost the innate immunotherapeutic efficacy. Resultantly, the developed simple MnOOH nanocatalytic medicine capable of simultaneously catalyzing GSH depletion and ROS generation, and mediating innate immune activation, holds great potential in the treatment of malignant tumors.

Hybrid nanogels by direct mixing of chitosan, tannic acid and magnetite nanoparticles: processes involved in their formation and potential catalytic properties.

Magnetite (Fe3O4) nanoparticles (MNPs) as nanocatalysts have drawn considerable attention because of their unique properties such as peroxidase-like activity. However, their biodistribution and availability for specific treatments still need to be improved. In this study, a simple and convenient strategy for the synthesis of hybrid nanogels (NGs) is described, which involves direct mixing of biomaterials such as chitosan (Ch) and tannic acid (TA), with the incorporation of MNPs, under oxidising conditions, using the inverse nanoemulsion method. The different processes involved in the formation of these hybrid nanosystems as well as their morphological and chemical structure are investigated using optical, spectroscopic, and electron microscopic techniques (DLS, UV-VIS, FT-IR, XPS, TEM, and SEM-EDS). It is demonstrated that ∼11 nm synthesized MNPs, post-functionalized with oxidised TA, act as covalent crosslinkers. As a proof of concept, the potential use of these materials in nanocatalytic medicine was evaluated using a colorimetric method based on the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in hydrogen peroxide. The results show that these hybrid nanogels have the same peroxidase-like activity as bare MNPs, indicating that the organic nanostructure stabilises the inorganic nanoparticles without any significant change in the catalytic properties. Therefore, this kind of nanomaterial has promising potential for use in nanocatalytic medicine with improved biocompatibility and biodistribution.

Platinum-based nanodendrites as glucose oxidase-mimicking surrogates.

Catalytic conversion of glucose represents an interesting field of research with multiple applications. From the biotechnology point of view, glucose conversion leads to the fabrication of different added-value by-products. In the field of nanocatalytic medicine, the reduction of glucose levels within the tumor microenvironment (TME) represents an appealing approach based on the starvation of cancer cells. Glucose typically achieves high conversion rates with the aid of glucose oxidase (GOx) enzymes or by fermentation. GOx is subjected to degradation, possesses poor recyclability and operates under very specific reaction conditions. Gold-based materials have been typically explored as inorganic catalytic alternatives to GOx in order to convert glucose into building block chemicals of interest. Still, the lack of sufficient selectivity towards certain products such as gluconolactone, the requirement of high fluxes of oxygen or the critical size dependency hinder their full potential, especially in liquid phase reactions. The present work describes the synthesis of platinum-based nanodendrites as novel enzyme-mimicking inorganic surrogates able to convert glucose into gluconolactone with outstanding selectivity values above 85%. We have also studied the enzymatic behavior of these Pt-based nanozymes using the Michaelis-Menten and Lineweaver-Burk models and used the main calculation approaches available in the literature to determine highly competitive glucose turnover rates for Pt or Pt-Au nanodendrites.

Single-walled carbon nanotube conjugated cytochrome c as exogenous nano catalytic medicine to combat intracellular oxidative stress.

Mitochondrial dysfunction has been reported to be one of the main causes of many diseases including cancer, type2 diabetes, neurodegenerative disorders, cardiac ischemia, sepsis, muscular dystrophy, etc. Under in vitro conditions, Cytochrome C (Cyt C) maintains mitochondrial homeostasis and stimulates apoptosis, along with being a key participant in the life-supporting function of ATP synthesis. Hence, the medicinal importance of Cyt C as catalytic defense is immensely important in various mitochondrial disorders. Here, we have developed a nanomaterial via electrostatically conjugating oxidized single-wall carbon nanotube with Cyt C (Cyt C@cSWCNT) for the exogenous delivery of Cyt C. The chemical and morphological characterization of the developed Cyt C@cSWCNT was done using UV-vis, FTIR, XPS, powder XRD, TGA/DSC, TEM, etc. The developed Cyt C@cSWCNT exhibited bifunctional catalase and peroxidase activity with Km (∼ 642.7 μM and 351.6 μM) and Vmax (∼0.33 μM/s and 2.62 μM/s) values, respectively. Also, through this conjugation Cyt C was found to retain its catalytic activity even at 60°C, excellent catalytic recyclability (at least up to 3 times), and wider pH activity (pH=3 to 9). Cyt C@cSWCNT was found to promote intracellular ROS quenching and maintain mitochondrial membrane potential and cellular membrane integrity via Na+/K+ ion homeostasis during the H2O2 stress. Overall the present strategy provides an alternative approach for the exogenous delivery of Cyt C which can be used as nano catalytic medicine.

Targeting acidogenic metabolism by engineering self-catalytic siRNA nanocarriers/nanocatalysts for amplified tumor apoptosis/ferroptosis

Nanocatalytic medicine holds great potential in inhibiting tumor progression based on the synergistic catalytic production of toxic reactive oxygen species (ROS) between fenton nanoagents and tumor-specific endogenous substances. However, the cellular self-antioxidant and detoxification mechanisms result in discounted cell killing effect of nanocatalytic therapeutics. In this work, we design and engineer an intelligent bimetallic-type metal-organic framework (MOF) nanosystem that facilitates efficient gene delivery and expression, consequently enabling dual regulation of intracellular acid metabolism and significant amplification of nanocatalytic tumor therapy through enhanced elicitation of apoptosis and ferroptosis. The endogenous RNA interference and exogenous acidic substances supplement concurrently elevated the intracellular acidity and amplified the nanocatalytic reactions-induced ferroptosis. Especially, the reduced intracellular pH-derived calcium influx caused mitochondrial calcium overload, rendering cancer cells highly susceptible to nanocatalysts-triggered oxidative stress apoptotic damage, resulting in significantly synergistic tumor suppression. This work demonstrates the concept of amplified ferroptosis/apoptosis induced by self-enhancing intelligent nanocatalytic tumor treatment through simultaneously co-targeting two specific cancer hallmarks.

Nanocatalytic bacteria disintegration reverses immunosuppression of colorectal cancer.

Tumor-associated bacteria (TAB) play a critically important role in regulating the microenvironment of a tumor, which consequently greatly deteriorates the therapeutic effects by chemo- and radiotherapy deactivation and, more considerably, leads to substantial immunosuppression. On the contrary, herein we propose a nanocatalytic tumor-immunotherapeutic modality based on the bacteria disintegration by bacteria-specific oxidative damage under magnetic hyperthermia for highly effective immune response activation-promoted tumor regression. A monodispersed and superparamagnetic nanocatalytic medicine modified by arginyl-glycyl-aspartic acid (RGD) and (3-carboxypropyl)triphenylphosphonium bromide (TPP), named as MNP-RGD-TPP herein, has been synthesized, which features selective accumulation at the TAB by the electrostatic affinity, enabling effective TAB disintegration by the nanocatalytic Fenton reaction producing abundant cytotoxic hydroxyl radicals in situ under alternating magnetic field-induced hyperthermia. More importantly, the lipopolysaccharide has been metabolically secreted from the destructed TAB as pathogen-associated molecular patterns (PAMPs) to M1-polarize tumor-associated macrophages (TAMs) and promote the maturation of dendritic cells (DCs) for innate immuno-response activation of TAMs, followed by cytotoxic T lymphocytes awakening under the PAMPs presentation by the mature DCs against tumor cells. The integrated innate and adaptive immunity activations based on this TAB-promoted nanocatalytic immunomedicine, instead of magnetic heating-induced hyperthermia or the released Fe2+/Fe3+ Fenton agent, has been found to achieve excellent therapeutic efficacy in an orthotopic colorectal cancer model, demonstrating the great potential of such an integrated immunity strategy in clinical tumor immunotherapy.

Mn-doped single atom nanozyme composited Au for enhancing enzymatic and photothermal therapy

As an emerging technology, nanocatalytic medicine attracts much attention, especially the ones according to the enzymatic reaction by using excess H2O2 in the tumor. Among various candidates, single-atom catalyst (SAC) revealed unique and outstanding redox reaction performance, since the active sites consisting of single metal atoms may achieve the maximum utilization of metal atoms and emerge obviously amplified reaction rate. Here we developed an M−Nx (M = Mn, Zn) center-based SAC with a hollow structure by calcination of Mn2+-doped zeolitic imidazolate frameworks (ZIF-8), and PEGylation was applied to improve the hydrophilicity. According to the enzymatic reaction, the M−Nx (M = Mn, Zn) centers have an inherent peroxidase-like activity to catalyze over-expressed H2O2 in the weak acidic tumor microenvironment and generate a large amount of toxic reactive oxygen species (ROS) like hydroxyl radicals for therapy. To keep efficient therapeutic output, we integrated the hollow SAC with Au which could expend the glucose in tumor and supply H2O2 as the substrate of peroxidase-like activity. Better yet, Au may boost the photothermal effect of SAC and offer another non-invasive photothermal therapy (PTT) to promote the effect of tumor removal. This platform provided a new idea for the construction of more efficient peroxidase-like activity in tumor therapy.

Blocking glutathione regeneration: Inorganic NADPH oxidase nanozyme catalyst potentiates tumoral ferroptosis

Emerging cancer cell ferroptosis features the direct depletion of glutathione (GSH) and resultant chemical inhibition on glutathione peroxidase 4 (GPX4) bioactivity, which, unfortunately, is counteracted considerably by nicotinamide adenine dinucleotide phosphate (NADPH)-enabled regeneration of antioxidant GSH. Herein, a Pt-MIL-101 (Fe)-based nanocatalytic medicine (NCM) is proposed to catalyze NADPH oxidation and the following nanozyme catalytic cascade reactions to produce hydroxyl radicals and prevent GSH regeneration, thus promoting the ferroptotic death of cancer cells. Briefly, the Pt-MIL-101 nanomedicine possessing NADPH oxidase (NOX)-like activity catalyzes the superoxide anions (O2•−) generation by promoting the electron transfer from NADPH to O2, followed by Pt-MIL-101-catalyzed O2•− disproportionation producing H2O2 using its superoxide dismutase (SOD) nanozyme catalytic activity. The generated H2O2 further serves as substrate for toxic ∙OH production via Fenton reaction with Fe3+/Fe2+ at the structure center of the MIL-101. Moreover, the NOX nanozyme-catalyzed NADPH depletion by the nanomedicine largely prevents the GSH regeneration and de-activates GPX4, promoting lipid peroxidation for ferroptotic cell death. This work highlights an effective NADPH-initiated nanozyme cascade nanocatalytic strategy for ferroptosis-based tumor therapy.

Cu-Doped Polypyrrole with Multi-Catalytic Activities for Sono-Enhanced Nanocatalytic Tumor Therapy.

Nanocatalytic medicine is a burgeoning disease treatment model with high specificity and biosafety in which the nanocatalyst is the core of driving catalytic reaction to generate therapeutic outcomes. However, the robust defense systems in the pathological region would counteract nanocatalyst-initiated therapeutics. Here, a Cu-doped polypyrrole is innovatively developed by a facile oxidative polymerization reaction, which exhibits intriguing multi-catalytic activities, including catalyzing H2 O2 to generate O2 and · OH, and consuming reduced glutathione by a Cu(II)-Cu(I) transition approach. By decorating with sonosensitizers and DSPE-PEG, the obtained CuPPy-TP plus US irradiation can induce severe oxidative damage to tumor cells by amplifying oxidative stress and simultaneously relieving antioxidant capacity in tumors based on the highly effective sonochemical and redox reactions. The notable tumor-specific biodegradability, remarkable cell apoptosis in vitro, and tumor suppression in vivo are demonstrated in this work, which not only present a promising biocompatible antitumor nanocatalyst but also broaden the perspective in oxidative stress-based antitumor therapy.

Acid Neutralization and Immune Regulation by Calcium–Aluminum-Layered Double Hydroxide for Osteoporosis Reversion

Osteoporosis is a kind of global chronic bone disease characterized by progressive loss of bone mass and bone quality reduction, leading to a largely increased risk of bone fragility. In clinics, the current treatment of osteoporosis relies on the inhibition of bone damage by osteoclasts but ignores the function of immune cells in the progress of osteoporosis, leading to much compromised therapeutic efficacy. In this work, a highly effective osteoporosis-immunotherapeutic modality is established for the treatment of osteoporosis based on acid neutralization in synergy with immune microenvironment regulation by a specially designed nanocatalytic medicine, calcein functionalized calcium-aluminum-layered double hydroxide (CALC) nanosheets. Briefly, the mildly alkaline CALC nanosheets could neutralize the acidic microenvironment of osteoporosis accompanying the acidity-responsive LDH degradation. Subsequently, calcium phosphate nanoparticles (CAPs) are generated by the reaction between the released Ca2+ from LDH degradation and endogenous phosphates, resulting in M2 phenotype anti-inflammatory differentiation of bone macrophages through a c-Maf transcriptional factor pathway and the following activity enhancements of regulatory T cells (Treg) and the deactivation of T helper 17 cells (TH17). Both in vitro and in vivo results show an excellent therapeutic efficacy on osteoporosis featuring a significant BV/TV (%) enhancement of femurs from 6.2 to 10.7, demonstrating high feasibility of this therapeutic concept through the combined acid neutralization and immune regulation. Such an inorganic nanomaterial-based strategy provides a novel, efficient, and biosafe therapeutic modality for intractable osteoporosis treatment, which will benefit patients suffering from osteoporosis.

Pyroptosis activation by photodynamic-boosted nanocatalytic medicine favors malignancy recession

Although pyroptosis as a newly-emerging but burgeoning programmed cell death fashion has been extensively accepted to outperform apoptosis in inducing rapid and complete cell deaths, potentiating immunity and mitigating resistance, its contribution is low. Therefore, the demand to elevate pyroptosis level is highly desirable and highlighted. Herein, a RGD-modified and pyroptosis-engineered theranostic agent (PETA) consisting of Fe3O4-embedded magnetic mesoporous silica nanoparticles (MMSN) vehicles and chlorin e6 (Ce6) photosensitizers (i.e., MMSN-cRGD@Ce6) is established to heighten ROS level for inducing pyroptosis by Ce6-mediated photodynamic process. Inspiringly, Fe3O4-mediated nanocatalytic medicine contributes to O2 release and hypoxia mitigation, which liberates hypoxia-induced resistances to ROS production and further favors ROS production. Consequently, ROS-activated pyroptosis is accessible to circumvent the hypoxia-induced resistance to ROS-activated apoptosis especially when uniting with cRGD-enhanced active targeting, which significantly represses malignant breast cancer in vitro and in vivo. The design principles of targeted PETAs can serve as a general method to develop new pyroptosis-highlighted theranostic agents, and coincidently indicate that pyroptosis contribution should be surveyed to veritably and comprehensively reflect death pathway when investigating ROS-based anti-tumor pathways.

A platinum-ruthenium hybrid prodrug with multi-enzymatic activities for chemo-catalytic therapy of hypoxic tumors.

Regulation of tumor hypoxia and redox homeostasis is a promising strategy for cancer therapy. Nanocatalytic medicine has played more and more important roles in this field because it can cleverly convert the efficiency and selectivity of catalysis into high therapeutic efficiency. Herein, we developed a platinum(iv)-ruthenium hybrid prodrug, named as Pt-Ru, for efficient chemo-catalytic synergistic therapy of hypoxic tumors. The ruthenium hybridization endowed the Pt(iv) prodrug with multi-enzyme catalytic activity, that is, mimicking catalase (CAT) to generate O2 in situ, mimicking peroxidase (POD) to produce reactive oxygen species, and mimicking glutathione peroxidase (GPx) to deplete GSH, thus effectively overcoming tumor hypoxia and cisplatin resistance. As a result, Pt-Ru treatment led to a superior anticancer efficacy to cisplatin both in vitro and in vivo. This work suggested redox homeostasis regulation as a tantalizing angle for developing the next generation of platinum drugs.

Carbon dots as nanocatalytic medicine for anti-inflammation therapy

Aberrant reactive oxygen species (ROS) generation is one of the crucial mediators in the pathogenesis of inflammation. So, the development of nanocatalytic medicine to catalyze the ROS-scavenging reactions in pathological regions are promising for anti-inflammatory therapy. Herein, a type of biocompatible metal free carbon dots is prepared via a hydrothermal method which can exhibit peroxidase (POD)-like, catalase (CAT)-like and superoxide dismutase (SOD)-like activities. It has been found that the carbon dots have the capability to efficiently deplete the excessive ROS such as peroxide (H2O2), superoxide anion (O2−) and hydroxyl radical (OH) for their abundant functional groups. After the tail injection in mice with liver inflammation induced by lipopolysaccharide, the carbon dots efficiently reduced the excessive production of ROS and proinflammatory cytokines in vitro. Both in vitro and in vivo results endowed the biocompatible carbon dots with great potential in nanocatalytic medicine for the treatment of disease.

Ligand Engineering of Titanium-Oxo Nanoclusters for Cerenkov Radiation-Reinforced Photo/Chemodynamic Tumor Therapy.

The therapeutic effect of general photodynamic therapy (PDT) is gravely limited by the poor penetration depth of exogenous light radiation. In recent years, Cerenkov radiation (CR) has been exploringly applied to overcome this critical defect. However, the currently reported type I photosensitizers for CR-induced PDT (CRIT) are only TiO2 nanoparticle-based agents with numerous fatally intrinsic drawbacks. Herein, we developed NH2-Ti32O16 nanocluster (NTOC)-derived ultrasmall nanophotosensitizers (NPSs, denoted as TDPs) via innovate ligand engineering. The introduced dopamine (DA) ligands not only facilitate the water solubility and photocatalytic properties of NPSs but also involve the tumor-targeting behavior through the binding affinity with DA receptors on cancer cells. Under CR irradiation, TDPs enable efficient hydroxyl radical (·OH) generation benefiting from the enhanced separation of hole (h+)-electron (e-) pairs, where the h+ will react with H2O to execute type I PDT and the transferred e- can realize the augmentation of Ti3+ to substantially promote the therapeutic index of chemodynamic therapy. This study provides an easy but feasible strategy for constructing versatile NPSs with an ultrasmall framework structure, propounding a refreshing paradigm for implementing efficient CR-induced combined therapy (CRICT) and spurring the development of CR and titanium-familial nanoplatforms in the fields of photocatalysis and nanocatalytic medicine.

Endogenous Copper for Nanocatalytic Oxidative Damage and Self-Protection Pathway Breakage of Cancer.

Nanocatalytic medicine is one of the most recent advances in the development of nanomedicine, which catalyzes intratumoral chemical reactions to produce toxins such as reactive oxygen species in situ for cancer specific treatment by using exogenous-delivered catalysts such as Fenton agents. However, the overexpression of reductive glutathione and Cu-Zn superoxide dismutase in cancer cells will significantly counteract the therapeutic efficacy by reactive oxygen species-mediated oxidative damages. Additionally, the direct delivery of iron-based Fenton agents may arouse undesired detrimental effects such as anaphylactic reactions. In this study, instead of exogenously delivering Fenton agents, the endogenous copper ions from intracellular Cu-Zn superoxide dismutase have been employed as the source of Fenton-like agents by chelating the Cu ions from the superoxide dismutase using a common metal ion chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN), followed by the TPEN-Cu(II) chelate reduction to TPEN-Cu(I) by reductive glutathione. Briefly, TPEN was loaded in a disulfide bond-containing link poly(acrylic acid) shell-coated hybrid mesoporous silica/organosilicate (MSN@MON) nanocomposite as a reductive glutathione-responsive nanoplatform, which features inter-related triple functions: intratumoral reductive glutathione-responsive link poly(acrylic acid) disruption and TPEN release; the accompanying reductive glutathione consumption and Cu-Zn superoxide dismutase deactivation by TPEN chelating Cu ions from this superoxide dismutase; and the Fenton reaction catalyzed by TPEN-Cu(I) chelate as a Fenton-like agent generated from TPEN-Cu(II) reduction by the remaining reductive glutathione in cancer cells, thereby cutting off the self-protection pathway of cancer cells under severe oxidation stress and ensuring cancer cell apoptosis by reactive oxygen species produced by the catalytic Fenton-like reactions. Such a nanocatalyst demonstrates excellent biosafety and augmented therapeutic efficacy by simultaneous nanocatalytic oxidative damage and intrinsic protection pathway breakage of cancer cells.