Chemodynamic Therapy Research Articles

Antibiotic-Augmented Chemodynamic Therapy for Treatment of Helicobacter pylori Infection in the Dynamic Stomach Environment.

Helicobacter pylori (H. pylori) is one of the main causes of peptic ulcer disease and gastric cancer. The overuse of antibiotics leads to bacterial drug resistance and disruption to the gut microbiome. Herein, a nanoparticle (TA-FeHMSN@Amox) was developed, comprising amoxicillin (Amox)-loaded iron-engineered hollow mesoporous silica as the core and a metal-polyphenol shell formed by tannic acid (TA) and Fe3+. In acidic stomach conditions, TA-FeHMSN@Amox generates bactericidal ·OH through Fenton/Fenton-like reactions of the degraded product Fe2+ and hydrogen peroxide (H2O2) at the infection site, achieving chemodynamic therapy (CDT). Moreover, released amoxicillin enhances therapeutic efficacy by impeding the self-repair of the bacterial cell wall damaged by CDT, overcoming the limitations of ineffective CDT under conditions lacking sufficient acidity and H2O2. The acidity-responsive CDT combined with reduced antibiotic usage ensures superior in vivo therapeutic efficacy and biocompatibility with intestinal flora, providing a highly potent strategy for treating H. pylori infections in the dynamic stomach environment.

Nanoplatform-based synergistic cancer Immuno-Chemodynamic therapy.

Immunotherapy has made excellent breakthroughs in the field of cancer treatments, but faces challenges with low immunogenicity of tumor cells and an immunosuppressive tumor microenvironment (ITME). The emerging chemodynamic therapy (CDT) based on the Fenton/Fenton-like reaction can induce immunogenic cell death (ICD) to enhance tumor immunogenicity, facilitating the transition from immune-cold to immune-hot tumors. Synergistic CDT and immunotherapy based on advanced nanotechnology have shown immense promise for improving therapeutic efficacy while minimizing side effects in cancer treatment. This review summarizes and discusses recent advances in the field, with the goal of designing a high-quality nanoplatform to enhance synergistic CDT in combination with immunotherapy and lay the foundation for its future clinical translation.

Advances in Carbon Dot Based Enhancement of Photodynamic Therapy of Tumors.

Photodynamic therapy has advantages of high selectivity, less invasiveness, and high lethality for cancer cells compared with traditional treatment methods. However, some problems have hindered the development of photodynamic therapy, such as limited penetration depth, lack of oxygen, and toxicity. Carbon dots are widely used in the imaging and treatment of tumors due to their excellent optical and physicochemical properties, so effective methods have been explored to address the issues in photodynamic therapy via carbon dots. This review aims to elucidate the role of carbon dots in photodynamic therapy of cancer. Moreover, we summarize and discuss some strategies to harness carbon dots to enhance photodynamic therapy. Finally, we summarize many cancer synergistic therapeutic modalities involving carbon dots such as chemodynamic therapy, photothermal therapy, and immunotherapy in combination with photodynamic therapy to achieve more effective and safer treatments.

Self-supply of hydrogen peroxide by a bimetal-based nanocatalytic platform to enhance chemodynamic therapy for tumor treatment

The tumor microenvironment (TME) is characterized by low pH, hypoxia, and overexpression of glutathione (GSH). Owing to the complexity of tumor pathogenesis and the heterogeneity of the TME, achieving satisfactory efficacy with a single treatment method is difficult, which significantly impedes tumor treatment. In this study, composite nanoparticles of calcium-copper/alginate-hyaluronic acid (HA) (CaO2-CuO2@SA/HA NC) with pH and GSH responsiveness were prepared for the first time through a one-step synthesis using HA as a targeting ligand. Nanoparticles loaded with H2O2can enhance the chemodynamic therapy effects. Simultaneously, Cu2+can generate oxygen in the TME and alleviate hypoxia in tumor tissue. Cu2+and H2O2undergo the Fenton reaction to produce cytotoxic hydroxyl radicals and Ca2+ions, which enhance the localization and clearance of nanoparticles in tumor cells. Additionally, HA and sodium alginate (SA) were utilized to improve the targeting and biocompatibility of the nanoparticles. Fourier transform infrared, x-ray diffraction, dynamic light scattering, SEM, transmission electron microscope, and other analytical methods were used to investigate their physical and chemical properties. The results indicate that the CaO2-CuO2@SA/HA NC prepared using a one-step method had a particle size of 220 nm, a narrow particle size distribution, and a uniform morphology. The hydrogen peroxide self-supplied nanodrug delivery system exhibited excellent pH-responsive release performance and glutathione-responsive •OH release ability while also reducing the level of reactive oxide species quenching.In vitrocell experiments, no obvious side effects on normal tissues were observed; however, the inhibition rate of malignant tumors HepG2 and DU145 exceeded 50%. The preparation of CaO2-CuO2@SA/HA NC nanoparticles, which can achieve both chemokinetic therapy and ion interference therapy, has demonstrated significant potential for clinical applications in cancer therapy.

Switchable ROS generator and scavenger to prevent the cisplatin induced acute kidney injury and improve efficacy via synergistic chemodynamic/immune therapy

Acute kidney injury (AKI) induced by cisplatin (DDP), which is accompanied with the generation of reactive oxygen species (ROS), is a severe side effect during treatment and restricts the application of DDP. In this study, we develop ultrasmall Mn3O4 nanozyme (UMON) with tumor microenvironment (TME) responsive ROS scavenging and generating as adjuvant to alleviate DDP induced AKI with improved efficacy. In kidney, UMON with superoxide dismutase and catalase activity acts as ROS scavenger to eliminate ROS generated by DDP, successfully protecting the renal cells/tissue and alleviating AKI during DDP treatment. Alternatively, UMON rapidly responses to the high GSH level in TME and release Mn2+ in tumor. This unique feature endows it to generate hydroxyl radicals (∙OH) through a Fenton-like reaction and deplete GSH in tumor cell and tissue, achieving high efficient chemodynamic therapy (CDT). More importantly, the Mn2+ successfully activates the cGAS-STING pathway, initiating the immune response and effectively inhibiting the tumor metastases. The synergistic CDT and immune therapy effectively improve the anti-tumor efficacy of DDP in vitro and in vivo. This study demonstrates that TME responsive ROS scavenger/generator shows the potential to reduce side effects of DDP while improve its therapeutic efficacy, providing a new avenue to achieve efficient chemotherapy and promoting the progress of clinical chemotherapy.

Molecular Photoswitching Unlocks Glucose Oxidase for Synergistically Reinforcing Fenton Reactions for Antitumor Chemodynamic Therapy.

We have developed a new type of nanoparticles with potent antitumor activity photoactivatable via the combination of molecular photoswitching of spiropyran (SP) and enzymatic reaction of glucose oxidase (GOx). As two key processes involved therein, Fe(III)-to-Fe(II) photoreduction in Fe(III) metal-organic frameworks (MOFs) brings about the release of free Fe2+/Fe3+ while the photoswitching of SP to merocyanine (MC) unlocks the enzymatic activity of GOx that was pre-passivated by SP. The release of free Fe3+ boosts its hydrolysis and therefore enables the acidification of microenvironment, which is further reinforced by one of the products of the GOx-mediated glucose oxidation reaction, gluconic acid (GlcA). Based on the generation of Fe2+ and acidic milieu together with another product of the oxidation reaction, hydrogen peroxide (H2O2), these two processes jointly present triple enabling factors for generating lethal hydroxyl radicals (⋅OH) species via Fenton reactions and therefore oxidative stress capable of inhibiting tumor. The antitumor potency of such nanoparticle is verified in tumor-bearing model mice in vivo, proclaiming its potential as a potent and safe agent based on the unique mechanism of optically manipulating enzyme activity for synergistic antitumor therapeutics with high spatial precision, enhanced efficacy and minimized side effects.

Photothermally Reinforced Nanozyme Remodeling Tumor Microenvironment of Redox and Metabolic Homeostasis to Enhance Ferroptosis in Tumor Therapy.

The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes' activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal-organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H2O2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H2O2 is generated during this procedure, which can endogenously replenish the consumed H2O2. Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H2O2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.

Recent Advances in Silica-Based Nanomaterials for Enhanced Tumor Imaging and Therapy.

Cancer remains a formidable challenge, inflicting profound physical, psychological, and financial burdens on patients. In this context, silica-based nanomaterials have garnered significant attention for their potential in tumor imaging and therapy owing to their exceptional properties, such as biocompatibility, customizable porosity, and versatile functionalization capabilities. This review meticulously examines the latest advancements in the application of silica-based nanomaterials for tumor imaging and therapy. It underscores their potential in enhancing various cancer imaging modalities, including fluorescence imaging, magnetic resonance imaging, computed tomography, positron emission tomography, ultrasound imaging, and multimodal imaging approaches. Moreover, the review delves into their therapeutic efficacy in chemotherapy, radiotherapy, phototherapy, immunotherapy, gas therapy, sonodynamic therapy, chemodynamic therapy, starvation therapy, and gene therapy. Critical evaluations of the biosafety profiles and degradation pathways of these nanomaterials within biological environments are also presented. By discussing the current challenges and prospects, this review aims to provide a nuanced perspective on the clinical translation of silica-based nanomaterials, thereby highlighting their promise in revolutionizing cancer diagnostics, enabling real-time monitoring of therapeutic responses, and advancing personalized medicine.

X-ray-triggered fenton-like nanocomposites for passive-activation and non-spontaneous chemodynamic therapy

Currently, many studies focused on the TME-regulating strategies to address the unsatisfactory therapeutic effect of single chemodynamic therapy (CDT). However, most of TME-regulating strategies were nonspecific, the CDT agents with spontaneous CDT activity would result in augmented killing effect not only in tumor but also in normal tissues. Furthermore, CDT efficiency was subject to attenuation due to the gradually exhausted active sites in CDT agents. Herein, the passive-activation and non-spontaneous CDT strategy was proposed by constructing a completely X-ray-triggered CDT agent (F-SCNPs) to target the therapeutic dilemma between the augmented CDT efficacy and high tumor specificity. In this study, the designed F-SCNPs can launch Fe2+ sites generation to initiate CDT activity only when they were exposed to X-ray, which were totally different from the traditional CDT agents including other stimuli-responsive CDT agents that always spontaneously exert CDT activity no matter they had accepted the stimuli or not. The X-ray-activated feature of F-SCNPs endowed their tumor specificity with less affect by nonspecific TME-regulating strategies. Meanwhile, X-ray can promote the Fe2+/Fe3+ cycling of F-SCNPs to enhance the •OH yield. This X-ray-mediated nanosystem with remarkable synergistic therapy of CDT and radiotherapy provided a promising avenue for high-efficiency and precise cancer treatments.

Manganese-doped liquid metal nanoplatforms for cellular uptake and glutathione depletion-enhanced photothermal and chemodynamic combination tumor therapy

Chemodynamic therapy (CDT) involves the catalysis of in situ overexpressed hydrogen peroxide (H2O2) into highly toxic reactive oxygen species (ROS) to treat tumors. However, the efficacy of CDT is greatly hampered by limited cellular internalization efficiency, ROS scavenging by glutathione (GSH), and slow reaction rate. To overcome the current limitations of CDT, a manganese-doped and polyethylene glycol (PEG)-modified liquid metal (LM)-silica nanoplatform (labeled as Mn-LMOP) with varying stiffness is constructed to achieve synergistic photothermal therapy (PTT) and CDT, which can further induce immunogenic cell death (ICD) in tumors to enhance the anti-tumour effects. Significantly, benefiting from the increased stiffness, the Mn-LMOP nanoparticles (NPs) can enhance cellular uptake and lysosomal escape, and gradually accumulate in tumor sites. Moreover, manganese-doped NPs exhibite good photothermal effects and can rapidly reacte with intratumoral GSH to produce Mn2+, inhibiting GSH-mediated ROS clearance and promoting the efficiency of CDT. This combined treatment strategy can activate the immune response of the tumors, which holds the promise of photothermal/chemodynamic/immune multimodal therapeutic effects. This LM-based nanosystem will provide a paradigm for enhanced CDT/PTT combination anti-tumour efficacy. Statement of significanceChemodynamic therapy (CDT) is a promising drug-free treatment approach characterized by its low invasiveness and minimal side effect. However, CDT encounters challenges such as high levels of glutathione (GSH), low Fenton-like reaction rate, and inefficient cellular uptake in tumor tissues. Here, a manganese-doped liquid metal (LM) nanomaterial was designed to achieve synergistic photothermal therapy (PTT) and CDT. This innovative strategy enhanced cellular uptake by adjusting the mechanical property of nanoparticles (NPs) and facilitated the consumption of GSH, while simultaneously accelerating the Fenton-like reaction rate with the assistance of PTT-mediated hyperthermia. This combined CDT/PTT strategy also activated the immune response within the tumor, demonstrating significant therapeutic potential.

DNA-templated nanosheets for enhanced chemodynamic therapy and gene therapy to inhibit tumor recurrence and metastasis

Recurrence and metastasis stand as the primary contributors to mortality among patients with triple-negative breast cancer post-surgery, presenting a formidable clinical obstacle. Chemodynamic therapy (CDT), leveraging metal-ion-mediated Fenton-like reactions within the tumor microenvironment (TME), emerges as a promising avenue for addressing cancer metastasis. Despite recent progress, challenges such as tumor cell antioxidant defenses and epithelial-mesenchymal transition (EMT) impede the efficacy of CDT. Here, we introduce a novel approach using DNA-templated nanosheets (Dz-MnO2) that combine the functions of Mn2+-mediated CDT and DNAzyme-mediated gene therapy to suppress tumor growth and metastasis. The Dz-MnO2 nanosheets respond effectively to the TME, releasing Mn2+ and DNAzyme. The DNAzyme exhibits mRNA cleavage activity, specifically targeting oncogenic transcripts to reduce tumor progression. Mn2+ not only facilitates a Fenton-like reaction, enhancing the chemodynamic treatment effect, but also serves as a cofactor for DNAzyme, improving its catalytic efficiency. Concurrently, the nanosheets robustly silence the Twist1 gene, mitigating the EMT process and reinforcing CDT efficacy by suppressing apoptosis resistance. Results indicate that Dz-MnO2 nanosheets efficiently polarize M2-tumor-associated macrophages (TAMs) into M1-TAMs by locally mitigating tumor hypoxia via catalyzing the decomposition of H2O2 into O2. This collaborative strategy presents a promising approach to enhance CDT, effectively inhibiting tumor recurrence and metastasis.

Pt loaded CoFe2O4-based nanoparticles for breast cancer treatment with chemodynamic therapy and sonodynamic therapy

Breast cancer is one of the most widespread cancers worldwide in the female population. However, the side effects and toxicity of chemotherapy and radiotherapy are the obstacles to the treatment of breast cancer. Therefore, we developed a Pt loaded CoFe2O4-based nanoparticles (CF@Pt) for breast cancer treatment with chemodynamic therapy (CDT) and sonodynamic therapy (SDT). The Co2+/Co3+ and Fe2+/Fe3+ gave CF@Pt peroxidase-like activity and catalase activity to gain ·OH and O2 in the tumor microenvironment (TME) for CDT. Furthermore, the separation of electron-hole pairs of CF@Pt transferred the O2 into 1O2 in the presence of ultrasound (US) for SDT. The high level of O2 generated by CDT would produce more 1O2 by SDT that promoted the CDT efficiency. Moreover, the addition of Pt limited the recombination of electron-hole pairs and reduced the energy gap to enhance SDT/CDT combination therapy. In addition, CF@Pt could be engulfed by MDA-MB-231 cells and induced the apoptosis while it had good biocompatibility and blood compatibility. This design provided a novel application on the treatment of breast cancer.

A multifunctional cascade gas-nanoreactor with MnO2 as a gatekeeper to enhance starvation therapy and provoke antitumor immune response

Glucose oxidase (GOx)-mediated starvation therapy is an effective tumor treatment that blocks energy and activates the immune response. However, the insufficient tumor immunogenicity and immunosuppressive tumor microenvironment (TME) limited its therapeutic efficacy. To address this, we have designed a multifunctional cascade gas-nanoreactor with a MnO2 coating, which serves as an out gatekeeper to encapsulate both GOx and a carbon monoxide (CO) donor (denoted as GCM). Due to the protective effect of MnO2 coating, GCM maintains better stability in normal physiological environments, enhancing the catalytic activity of GOx and minimizing toxic side effects. Upon accumulation in the tumor, the degradation of MnO2 coating exposes the GOx enzyme, thereby initiating a cascade catalysis reaction to generate hydrogen peroxide (H2O2) and release CO in the hypoxic conditions. Additionally, the released Mn2+ reacts with H2O2 to generate toxic hydroxyl radical (•OH) as chemodynamic therapy (CDT). The synergistic treatments of starvation therapy, CO gas therapy and CDT effectively kill cancer cells and amplify immunogenic cell death (ICD), maturing DC cells and activating anti-tumor immune response. Furthermore, the released CO increases M1 macrophages infiltration and reduces myeloid-derived suppressor cells (MDSCs) infiltration, thus reversing the immunosuppressive TME. This multifunctional gas-nanoreactor provides a strategy for CO gas generation to trigger a robust anti-tumor immune response and has the potential for clinical application in cancer immunotherapy. Statement of significanceA multifunctional cascade gas-nanoreactor with a MnO2 gatekeeper was developed to perform synergistic treatments involving starvation therapy, CO gas therapy and chemodynamic therapy (CDT) for tumor elimination. The MnO2 gatekeeper enhanced the catalytic activity of GOx within the nanoreactor by generating oxygen, thereby minimizing toxic side effects after intravenous injection. The gas-nanoreactor amplified ICD through synergistic treatments to mature DC cells and activate anti-tumor immune response. Furthermore, the released CO could reverse the immunosuppression of the TME to enhance cancer immunotherapy. The combination strategy utilizing the gas-nanoreactor demonstrates clinical potential for facilitating cancer immunotherapy.

Proton nanomodulators for enhanced Mn2+-mediated chemodynamic therapy of tumors via HCO3− regulation

BackgroundMn2+-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO3− level in the system. Although the physiological buffers (H2CO3/HCO3−) provide certain amounts of HCO3−, the acidity of the tumor microenvironment (TME) would seriously affect the HCO3− ionic equilibrium (H2CO3 ⇌ H+ + HCO3−). As a result, HCO3− level in the tumor region is actually insufficient to support effective Mn2+-mediated CDT.ResultsIn this study, a robust nanomodulator MnFe2O4@ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO3− is presented to enhance therapeutic efficacy of Mn2+-mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO3− ionic equilibrium to the positive direction, significantly boosting the generation of the HCO3−. Most importantly, such HCO3− supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFe2O4 of PrSMZ to exert the remarkable antitumor effect on mouse models.ConclusionsThis work addresses the challenge of insufficient HCO3− in the TME for Mn2+-mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn2+-mediated CDT agents to treat cancer effectively.

An injectable dual-layer chitosan-alginate nano-hydrogel incorporated Cu(I)-isopolymolybdate-based metal-organic framework tailored for three-in-one anti-cancer nanotherapy

Designing potential agents and constructing hydrophilic nano-hydrogel platforms for biomedical and pharmaceutical applications, especially for polyoxometalate-based metal-organic frameworks (PMOF), present both great desirability and significant challenges. A unique open porous Cu(I)-isopolymolybdate-based metal-organic framework (CCUT) has been self-assembled through ionothermal processes for in vivo synergistic anti-cancer therapy. The periodicity of Drugs@CCUT-1 (nano-crystals of CCUT after cation exchange and anti-cancer drugs upload) has been investigated by synchrotron wide-angle X-ray scattering, confirming the lattice structure unchanged. To mitigate toxicity, enhance stimuli-responsive drug delivery, hydrophilicity, and biocompatibility, an injectable dual-layer chitosan//alginate-based nano-hydrogel is developed to incorporate Drugs@CCUT-1. Potential interactions between the chitosan layer and the surface of CCUT-1 have been analyzed by Density Functional Theory (DFT). Furthermore, the nanoparticles Drugs@CCUT-1@Gel exhibit efficient type I photodynamic therapy (PDT) and chemodynamic therapy (CDT) within the bio-window, effectively eradicating tumors in deep tissue. CCUT-1 generates a substantial amount of reactive oxygen species (ROS), stimulating the Keap1-Nrf2 signaling pathway and resulting in the expression of phase II enzymes, typically HO-1. CCUT-1@Gel not only demonstrates high capacity for anti-cancer drug upload and release, but also exhibits strong synergistic CDT/PDT in vivo anti-tumor efficacy. Hence, CCUT-1@Gel represents a promising in vivo nano-platform for synergistic chemotherapy (CT)/CDT/PDT three-in-one anti-cancer approach.

Metal-Phenolic Networks: A Promising Frontier in Cancer Theranostics.

The burgeoning field of cancer theranostics has been significantly advanced by the development of Metal-Phenolic Networks (MPNs), a new class of supramolecular architectures that integrate the advantages of metals and polyphenols. This review focuses on MPNs and their promising applications in cancer theranostics. Through a systematic literature search spanning from 2010 to 2023 in databases including PubMed, Scopus, and Web of Science. The period of search was justified by the rapid evolution of nanomaterials in cancer therapy, with MPNs emerging as a significant player in biomedical applications within the specified timeframe. This review discusses the classification and structure of polyphenolic compounds, as well as their mechanisms of action in cancer treatment. The applications of MPNs in chemotherapy drug delivery, photothermal therapy, chemodynamic therapy, biomedical imaging, and synergistic therapy are especially detailed. The authors emphasize the significance of MPNs in cancer nanomedicine and look forward to their future development directions.

PH-activated metal–organic layer nanozyme for ferroptosis tumor therapy

Nanozymes have made great achievements in the research of tumor therapy. However, due to the complex tumor microenvironment, the catalytic activity and biosafety of nanozymes are limited. High catalytic efficiency is a relentless pursuit for the preparation of high-performance nanozymes. Dimensional reduction from 3D nanoscale metal–organic frameworks (nMOFs) to 2D nanoscale metal–organic layers (nMOLs) increases the encounters frequency of nanozymes and substrate, which facilitates the diffusion of reactive oxygen species (ROS) from nMOLs, thus significantly improving the effectiveness of chemodynamic therapy. In this study, He@Ce-BTC nMOF and He@Ce-BTB nMOL based on Ce6 SBUs were synthesized by solvothermal reaction. Compared with the 3D nMOFs, the 2D nanozymes He@Ce-BTB nMOL possessed enhanced ROS catalytic efficiency, were able to be activated by the tumor acidic microenvironment with the polymerase mimetic activities (CAT, POD, GSH-OXD) that enhances the lipid peroxidation process and accelerates the process of ferroptosis thereby killing tumor cells. In addition, He@Ce-BTB does not affect normal tissue cells, thus avoiding diffusion-induced side effects. He@Ce-BTB has shown excellent therapeutic effects in vitro and in vivo, which indicates its potential for clinical application, and is expected to become a new generation of drugs for the treatment of tumors.

High Entropy 2D Layered Double Hydroxide Nanosheet Toward Cascaded Nanozyme-Initiated Chemodynamic and Immune Synergistic Therapy.

High-entropy nanomaterials (HEMs) are a hot topic in the fields of energy and catalysis. However, in terms of promising biomedical applications, potential therapeutic studies involving HEMs are unprecedented. Herein, we demonstrated high entropy two-dimensional layered double hydroxide (HE-LDH) nanoplatforms with versatile physicochemical advantages that reprogram the tumor microenvironment (TME) and provide antitumor treatment via cascaded nanoenzyme-initiated chemodynamic and immune synergistic therapy. In response to the TME, the multifunctional HE-LDHs sequentially release metal ions, such as Co2+, Fe3+, and Cu2+, exhibiting exquisite superoxide dismutase (SOD), peroxidase (POD), and glutathione peroxidase (GPX) activities. The multiple enzymatic activities convert specific tumor metabolites into a continuous supply of cytotoxic reactive oxygen species (ROS) to relieve hypoxia under a TME. Thus, HE-LDHs facilitate robust nanozyme-initiated chemodynamic therapy (NCDT), achieving high therapeutic efficacy without obvious side effects. In addition, the release of Zn2+ from the HE-LDH matrix triggers the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) signaling pathway, boosting the innate immunotherapeutic efficacy. The intratumoral applications of the nanocomposite in tumor-bearing mice models indicate that HE-LDH-mediated NCDT and immune synergistic therapy effectively upregulated the expression of relevant antitumor cytokines and induced cytotoxic T lymphocyte infiltration, showing superior efficacy in inhibiting tumor growth. Therefore, this work opens a new research direction toward synchronized NCDT and immunotherapy of tumors using HEMs for advanced healthcare.

Nanoarchitectonics of Copper Sulfide Nanoplating for Improvement of Computed Tomography Efficacy of Bismuth Oxide Constructs towards Drugless Theranostics

Abstract Triple-negative breast cancer (TNBC) has emerged as one of the dreadful metastatic tumors in women due to complexity, specificity, and high recurrence, resulting in poor therapeutic outcomes and requiring real-time monitoring for improved theranostics. Despite the success as efficient radiosensitizers and computed tomography (CT)-based contrast agents, bismuth (Bi)-based composites suffer from poor colloidal stability, dose-dependent toxicity, and pharmacokinetic shortcomings, leading to poor therapeutic monitoring. In addition, several small molecule-based therapeutics, including nanoparticle-based delivery systems, suffer from several limitations of poor therapeutic delivery and acquired multidrug resistance by cancer cells, depriving the therapeutic needs. To overcome this aspect, this study demonstrates the fabrication of drug-like/drugless nanoarchitectures based on copper sulfide-nanoplated bismuth oxide (Bi2O3@CuS, shortly BC) composites for improved theranostic efficacy against TNBC. These systematically characterized BC nanocomposites exhibited pH-/near-infrared (NIR, 808 nm) light-responsive degradability towards dual modal therapies. Due to the band transition of Cu species, the designed BC composites displayed exceptional photothermal (PTT) conversion efficiency towards localized PTT effects. In addition to pH-/NIR-responsiveness, the internally overexpressed glutathione (GSH)-responsiveness facilitated the release of Cu2+ species for chemodynamic therapy (CDT) effects. To this end, the Bi3+ species in the core could be fully hydrated in the acidic tumor microenvironment (TME), resulting in GSH depletion and reducing CDT-induced reactive oxygen species (ROS) clearance, thereby ablating tumors. The acid-responsive degradability of CuS resulted in the intratumoral enrichment of BC, demonstrating remarkable CT imaging efficacy in vivo. Together, these pH-/NIR-/GSH-responsive biodegradable BC composites could realize the integrated PTT/CDT/CT theranostics against breast carcinoma.

Tumor therapy utilizing dual-responsive nanoparticles: A multifaceted approach integrating calcium-overload and PTT/CDT/chemotherapy

The advancement of rational nano drug delivery systems offers robust tools for achieving synergistic therapeutic outcomes in tumor treatment. In this study, we present the development of pH and near-infrared laser dual-responsive nanoparticles (DOX-CuS@CaCO3@PL-PEG, DCCP NPs) based on calcium carbonate, utilizing a one-pot gas diffusion reaction. These nanoparticles enable combined photothermal therapy (PTT), chemodynamic therapy (CDT), chemotherapy, and Ca2+-overloading synergistic therapy. Doxorubicin (DOX) and copper sulfide (CuS) NPs were co-loaded in CaCO3, followed by PEG surface functionalization. The presence of PEG enhanced the stability of DCCP NPs in aqueous environments. Controlled release of DOX, CuS NPs, and Ca2+ occurs specifically in the acidic tumor microenvironment. Released DOX enhances chemotherapy efficiency, while CuS NPs, upon laser irradiation, induce thermal damage, promoting further drug release and cellular uptake. Additionally, CuS NPs in our system consume excess GSH and generate toxic hydroxyl radicals (·OH) through a Fenton-like reaction, contributing to CDT. These radicals not only directly eliminate tumor cells but also disrupt mitochondrial Ca2+ buffering capacity. Furthermore, Ca2+ released from CaCO3 induces Ca2+-overloading, intensifying mitochondrial disruption and oxidative damage. The synergistic combination of PTT, CDT, chemotherapy, and Ca2+-overloading showcases significant therapeutic potential, indicating broad applications in tumor therapy. This multifaceted approach holds promise for advancing the field of tumor therapeutics.