Efficacy Of Chemodynamic Therapy Research Articles

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.

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.

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.

Photothermally reinforced chemodynamic therapy in the treatment of osteosarcoma by polydopamine-modified, copper peroxide loaded ZIF8 nanoparticles

Chemodynamic therapy (CDT) has played an important role in osteosarcoma (OS) treatment. However, the insufficient content of endogenous H2O2 and high expression of glutathione (GSH) in tumor tissues limit the antitumor efficacy of CDT. In this work, we developed polydopamine (PDA) coated and CuO2 NPs loaded ZIF8 nanoparticles (CuO2@ZIF8@PDA NPs) for thermally reinforced CDT treatment of OS. The CuO2@ZIF8@PDA NPs exhibited excellent stability in neutral solutions while degraded in weakly acidic environments to generate hydrogen peroxide (H2O2) and Cu2+. Cu2+ consumes GSH in tumor tissues to generate Cu+. Both Cu2+ and Cu+ catalyzed the decomposition of H2O2, triggering a Fenton-like reaction to produce hydroxyl radicals (•OH). The PDA coating endowed the nanosystem with photothermal conversion capabilities under near-infrared laser irradiation, further promoting the generation of •OH, and inducing tumor cell death. In vitro experiments demonstrated that CuO2@ZIF8@PDA NPs exhibited significant toxicity towards K7M2 cells while remaining non-toxic to normal cells. In vivo studies revealed that under 808 nm laser irradiation, CuO2@ZIF8@PDA NPs exhibited stronger killing ability against K7M2 cells than CuO2@ZIF8@PDA NPs alone. This system, which combines GSH depletion, intratumoral H2O2 self-generation, and photothermally enhanced CDT, holds great promise for playing a pivotal role in the treatment of osteosarcoma.

A Functional "Key" Amplified Piezoelectric Effect Modulates ROS Storm with an Open Source for Multimodal Synergistic Cancer Therapy.

Chemodynamic therapy (CDT) is a non-invasive strategy for generating reactive oxygen species (ROS) and is promising for cancer treatment. However, increasing ROS in tumor therapy remains challenging. Therefore, exogenous excitation and inhibition of electron-hole pair recombination are attractive for modulating ROS storms in tumors. Herein, a Ce-doped BiFeO3 (CBFO) piezoelectric sonosensitizer to modulate ROS generation and realize a synergistic mechanism of CDT/sonodynamic therapy and piezodynamic therapy (PzDT) is proposed. The mixed Fe2+ and Ce3+ can implement a circular Fenton/Fenton-like reaction in the tumor microenvironment. Abundant ·OH can be generated by ultrasound (US) stimulation to enhance CDT efficacy. As a typical piezoelectric sonosensitizer, CBFO can produce O2 - owing to the enhanced polarization by the US, resulting in the motion of charge carriers. In addition, CBFO can produce a piezoresponse irradiated upon US, which accelerates the migration rate of electrons/holes in opposite directions and results in energy band bending, further achieving toxic ROS production and realizing PzDT. Density functional theory calculations confirmed that Ce doping shortens the diffusion of electrons and improves the conductivity and catalytic activity of CBFO. This distinct US-enhanced strategy emphasizes the effects of doping engineering and piezoelectric-optimized therapy and shows great potential for the treatment of malignant tumors.

NIR-II triggered Cu(I) phosphide for chemodynamic and photothermal periodontitis treatment: Efficient reduction of bacterial co-aggregation

The synergy between chemodynamic therapy (CDT) and photothermal therapy (PTT) offers a promising antimicrobial strategy for periodontitis, yet faces challenges like complex material structure and limited NIR-I light penetration. Additionally, low endogenous H2O2 levels in biofilm and a focus on bacterial eradication over colonization prevention limit current treatments. To address these issues, we newly introduce a single-material system (Cu3P@PAH@Lox) that integrates dual functionalities to synergistically enhance antimicrobial effects and significantly reduce pathogen co-aggregation. This system utilizes PTT to increase local temperature, boosting •OH production in CDT while downregulating heat shock proteins to enhance PTT efficacy, forming a self-reinforcing feedback loop. Lactate oxidase (Lox) is employed to convert lactate—a metabolite in periodontal biofilm—into H2O2, further amplifying CDT's potential. In vitro Cu3P@PAH@Lox demonstrates a remarkable synergistic effect against dual-species biofilms by more than 2-log reduction of colony-forming unit. Moreover, Cu3P@PAH@Lox exhibits outstanding synergistic antibacterial performances to alleviate inflammation and destruction of tissue in vivo periodontitis model. Furthermore, the mechanism of pathogen co-aggregation disruption by PTT is verified via the Cbe-Ltp1-Ptk1-fimA signaling pathway. This single-material multimodal system we have herein demonstrated for the first time marks a significant advancement in periodontitis treatment, eradicating microbes and preventing bacterial colonization, offering a path to comprehensive periodontal care. Statement of significanceThe synergy between chemodynamic therapy (CDT) and photothermal therapy (PTT) has been considered a promising therapy for periodontitis. Yet, facing challenges, the complex material structure, limited NIR-I light penetration, low endogenous H2O2 level in biofilm, and a focus on bacterial eradication over colonization prevention are still insufficient. This study pioneers a unique, single-material system (Cu3P@PAH@Lox) that synergistically enhances antimicrobial effects and substantially curtails pathogen co-aggregation, advancing periodontitis therapy. By exploiting PTT to elevate local temperatures, thereby increasing hydroxyl radical production in CDT and concurrently suppressing heat shock proteins, the system establishes a potent, self-enhancing loop. Furthermore, lactate oxidase is innovatively utilized to convert lactate from periodontal biofilm into hydrogen peroxide, augmenting the efficacy of CDT. The introduction of Cu3P@PAH@Lox is poised to revolutionize periodontitis treatment, eliminating microbes and impeding bacterial colonization, thereby charting a course for comprehensive periodontal management.

Dual-enzyme inhibiting nanomedicines for enhanced cancer chemodynamic therapy by inducing intratumoral acidosis

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.

Supramolecular assembly of Polydopamine@Fe nanoparticles with near-infrared light-accelerated cascade catalysis applied for synergistic photothermal-enhanced chemodynamic therapy

Chemodynamic therapy (CDT) via Fenton-like reaction is greatly attractive owing to its capability to generate highly cytotoxic •OH radicals from tumoral hydrogen peroxide (H2O2). However, the antitumor efficacy of CDT is often challenged by the relatively low radical generation efficiency and the high levels of antioxidative glutathione (GSH) in tumor microenvironment. Herein, an innovative photothermal Fenton-like catalyst, Fe-chelated polydopamine (PDA@Fe) nanoparticle, with excellent GSH-depleting capability is constructed via one-step molecular assembly strategy for dual-modal imaging-guided synergetic photothermal-enhanced chemodynamic therapy. Fe(III) ions in PDA@Fe nanoparticles can consume the GSH overexpressed in tumor microenvironment to avoid the potential •OH consumption, while the as-produced Fe(II) ions subsequently convert tumoral H2O2 into cytotoxic •OH radicals through the Fenton reaction. Notably, PDA@Fe nanoparticles demonstrate excellent near-infrared light absorption that results in superior photothermal conversion ability, which further boosts above-mentioned cascade catalysis to yield more •OH radicals for enhanced CDT. Taken together with T1-weighted magnetic resonance imaging (MRI) contrast enhancement (r1 = 8.13 mM−1 s−1) and strong photoacoustic (PA) imaging signal of PDA@Fe nanoparticles, this design finally realizes the synergistic photothermal-chemodynamic therapy. Overall, this work offers a new promising paradigm to effectively accommodate both imaging and therapy functions in one well-defined framework for personalized precision disease treatment.

Injectable Therapeutic Hydrogel with H2O2 Self-Supplying and GSH Consumption for Synergistic Chemodynamic/Low-Temperature Photothermal Inhibition of Postoperative Tumor Recurrence and Wound Infection.

Postoperative tumor recurrence and wound infection remain significant clinical challenges in surgery, often requiring adjuvant therapies. The combination treatment of photothermal therapy (PTT) and chemodynamic therapy (CDT) has proven to be effective in cancer treatment and wound infection. However, the hyperthermia during PTT increases the risk of normal tissue damage, severely impeding its application. Moreover, the efficacy of CDT is limited by insufficient hydrogen peroxide (H2O2) and excessive glutathione (GSH) levels at tumor or infection sites. Herein, an injectable and multifunctional CuO2@Au hydrogel system (CuO2@Au Gel) is developed for synergistic CDT and low-temperature PTT (LTPTT) to prevent tumor recurrence and bacterial wound infections. CuO2@Au Gel is constructed by embedding therapeutic CuO2@Au into low-melting point agarose hydrogel. In vitro and in vivo experiments confirm that the CuO2@Au in CuO2@Au Gel is capable of self-supplying H2O2 and depleting GSH, exhibiting effective CDT effect in acidic tumor or bacterial infected microenvironment. Additionally, it exhibits favorable photothermal conversion ability, inducing localized temperature elevation and synergistically enhancing CDT efficiency. The prepared CuO2@Au Gel demonstrates efficient tumor ablation capability in post-surgery recurrence mouse models and exhibits promising anti-infective efficiency in bacterial infection wound models, indicating significant potential in adjuvant therapy for post-surgical treatment and recovery.

Dendrimer/metal-phenolic nanocomplexes encapsulating CuO2 for targeted magnetic resonance imaging and enhanced ferroptosis/cuproptosis/chemodynamic therapy by regulating the tumor microenvironment

The combination of ferroptosis, cuproptosis, and chemodynamic therapy (CDT) would be a potential strategy for tumor diagnosis and enhanced treatment. However, the therapeutic effect was severely limited by the lack of specific delivery of catalytic ions and the low Fenton reaction efficiency in tumor microenvironment (TME) with excess glutathione, limited acidity and insufficient endogenous hydrogen peroxide. In this work, p-carboxybenzenesulfonamide (BS), a carbonic anhydrase IX (CA IX) inhibitor, was modified on the surface of generation-5 poly(amidoamine) dendrimer to load copper peroxide nanoparticles, which were complexed with iron (Fe)-tannic acid (TF) networks for targeted magnetic resonance (MR) imaging and enhanced ferroptosis/cuproptosis/CDT by regulating TME. The formed CuO2@G5-BS/TF nanocomplexes with an average size of 39.4 nm could be specifically accumulated at tumor site and effectively internalized by metastatic 4T1 cells via the specific interaction between BS and CA IX over-expressed on tumor cells. Meanwhile, the inhibition of CA IX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H2O2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity in TME. Moreover, the reduction of Fe3+/Cu2+ by intracellular glutathione (GSH) could further amplify ROS generation and enhance CDT efficacy, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy. In vivo experimental results demonstrated that CuO2@G5-BS/TF could provide better tumor MR imaging, effectively inhibit the growth and metastasis of 4T1 breast tumors, and be metabolized without significant systemic toxicity. Thus, CuO2@G5-BS/TF nanocomplexes provided a new approach for targeted MR imaging and enhanced ferroptosis/cuproptosis/CDT of triple-negative breast cancer. Statement of significanceTaking the advantage of dendrimer and metal-phenolic system, stable CuO2@G5-BS/TF nanocomplexes with an average size of 39.4 nm were synthesized to efficiently load Fe3+ and CuO2 nanoparticles for TNBC treatment and MR imaging. CuO2@G5-BS/TF nanocomplexes could target tumor cells overexpressing CAIX via the specific binding with BS, and the inhibition of CAIX activity could not only decrease the intracellular pH to accelerate Fe3+/Cu2+ release, H2O2 self-supply and Fenton reaction, but also suppress tumor metastasis by alleviating the extracellular acidity. The reduction of Fe3+/Cu2+ by intracellular GSH could further amplify ·OH generation, and the GSH depletion could in turn inhibit GPX-4 mediated antioxidant reaction to induce ferroptosis, resulting in effective therapeutic efficacy by enhanced ferroptosis/cuproptosis/CDT via tumor microenvironment regulation.

Emerging Chemodynamic Nanotherapeutics for Cancer Treatment.

Chemodynamic therapy (CDT) has emerged as a transformative paradigm in the realm of reactive oxygen species -mediated cancer therapies, exhibiting its potential as a sophisticated strategy for precise and effective tumor treatment. CDT primarily relies on metal ions and hydrogen peroxide to initiate Fenton or Fenton-like reactions, generating cytotoxic hydroxyl radicals. Its notable advantages in cancer treatment are demonstrated, including tumor specificity, autonomy from external triggers, and a favorable side-effect profile. Recent advancements in nanomedicine are devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy. This review systematically elucidates cutting-edge achievements in chemodynamic nanotherapeutics, exploring strategies for enhanced Fenton or Fenton-like reactions, improved tumor microenvironment modulation, and precise regulation in energy metabolism. Moreover, a detailed analysis of diverse CDT-mediated combination therapies is provided. Finally, the review concludes with a comprehensive discussion of the prospects and intrinsic challenges to the application of chemodynamic nanotherapeutics in the domain of cancer treatment.

EGCG-vanadium nanomedicine with neutral pH Fenton reaction activity inhibits heat shock proteins for enhanced photothermal/chemodynamic therapy

A burgeoning interest has recently focused on the development of nanomedicine to integrate noninvasive photothermal therapy (PTT) and chemodynamic therapy (CDT) for synergistic tumor treatments, owing to PTT's amplification effect on CDT. However, challenges emerge as hyperthermia often induces an unwarranted overexpression of cytoprotective heat shock proteins (HSPs), thereby curtailing PTT efficacy. Additionally, the nearly neutral tumor intracellular pH (pHi ≈ 7.2) that handicaps the Fenton reaction poses a leading limitation to CDT. Addressing these hurdles, we introduce EVP, a nanomedicine developed through the straightforward assembly of epigallocatechin gallate (EGCG), vanadium sulfate (VOSO4), and Pluronic F-127 (PF127). EVP comprehensively downregulates overexpressed HSPs (HSP 60, 70, 90) through the collaborative action of EGCG and vanadyl (VO2+). Moreover, the tumor intracellular pH-processed Fenton-like reaction by VO2+ ensures highly efficient hydroxyl radicals (OH) production in cytosols, overcoming the stringent acidity requirement for CDT. Additionally, the hyperthermia induced by PTT augments OH production, further enhancing CDT efficacy. In vitro and in vivo experiments validate EVP's excellent biocompatibility and potent tumor inhibition, highlighting its substantial potential in tumor therapy.

Improving Magnetic Resonance Imaging and Chemodynamic Therapy Properties via Tuning the Fe(II)/Fe(III) Ratio in Hydrophilic Single-Atom Nanobowls.

We developed an intrinsic hydrophilic single-atom iron nanobowl (Fe-SANB) for magnetic resonance imaging (MRI)-guided tumor microenvironment-triggered cancer therapy. Benefiting from the sufficient exposure of Fe single atoms and the intrinsic hydrophilicity of the bowl-shaped structure, the Fe-SANBs exhibited a superior performance for T1-weighted MRI with an r1 value of 11.48 mM-1 s-1, which is 3-fold higher than that of the commercial Gd-DTPA (r1 = 3.72 mM-1 s-1). After further coembedding Gd single atoms in the nanobowls, the r1 value can be greatly improved to 19.54 mM-1 s-1. In tumor microenvironment (TME), the Fe-SANBs can trigger pH-induced Fenton-like activity to generate highly toxic hydroxyl radicals for high-efficiency chemodynamic therapy (CDT). Both the MRI and CDT efficiency of these nanobowls can be optimized by tuning the ratio of Fe(II)/Fe(III) in the Fe-SANBs via controlling the calcination temperature. Furthermore, the generation of •OH at the tumor site can be accelerated via the photothermal effect of Fe-SANBs, thus promoting CDT efficacy. Both in vitro and in vivo results confirmed that our nanoplatform exhibited high T1-weighted MRI contrast, robust biocompatibility, and satisfactory tumor treatment, providing a potential nanoplatform for MRI-guided TME-triggered precise cancer therapy.

H2O2 self-supplying and GSH-depleting nanosystem for amplified NIR mediated-chemodynamic therapy of MRSA biofilm-associated infections

Reactive oxygen species (ROS) has emerged as potent therapeutic agents for biofilm-associated bacterial infections. Chemodynamic therapy (CDT), involving the generation of high-energy ROS, displays great potential in the therapy of bacterial infections. However, challenges such as insufficient hydrogen peroxide (H2O2) and over-expressed glutathione (GSH) levels within the microenvironment of bacterial biofilms severely limit the antibacterial efficacy of CDT. Herein, we have developed a multifunctional nanoplatform (CuS@CaO2@Dex) by integrating copper sulfide (CuS) and calcium peroxide (CaO2) into dextran (Dex)-coated nanoparticles. This innovative platform enhanced ROS generation for highly efficient biofilm elimination by simultaneously supplying H2O2 and depleting GSH. The Dex-coating facilitated the penetrability of CuS@CaO2@Dex into biofilms, while CaO2 generated a substantial amount of H2O2 in the acidic biofilm microenvironment. CuS, through a Fenton-like reaction, catalyzed the conversion of self-supplied H2O2 into hydroxyl radicals (•OH) and consumed the overexpressed GSH. Additionally, the incorporation of near-infrared II (NIR II) laser irradiation enhanced the photothermal properties of CuS, improving the catalytic efficiency of the Fenton-like reaction for enhanced antibacterial effects. In vivo experiments have demonstrated that CuS@CaO2@Dex exhibited remarkable antibacterial and antibiofilm efficacy, exceptional wound healing capabilities, and notable biosafety. In summary, the Dex-coated nanoplatform proposed in this study, with its self-sterilization capability through ROS, holds significant potential for future biomedical applications.

Fe(III)-juglone nanoscale coordination polymers for cascade chemodynamic therapy through synergistic ferroptosis and apoptosis strategy

Chemodynamic therapy (CDT) relying on the transformation of endogenous hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (·OH) based on the catalysis of Fenton/Fenton-type reactions exhibits great potentiality for cancer treatment. However, the inadequate H2O2 supply and intricate redox homeostasis in tumor microenvironment (TME) severely impair the efficacy of CDT. Herein, we design self-assembled 1,2-distearoyl-sn‑glycero-3-phosphoethanolamine conjugated polyethylene glycol (DSPE-PEG)-modified Fe(III)-juglone nanoscale coordination polymers (FJP NCPs) as redox homeostasis disruptors for juglone-enhanced CDT. Responding to glutathione (GSH)-rich and acidic TME, the Fe2+/Fe3+-guided CDT and GSH consumption by Fe3+ are activated, resulting in ·OH downstream and up-regulation of lipid peroxidation (LPO). In addition, the released juglone not only depletes GSH through Michael addition, but also elevates intracellular H2O2 level for achieving ·OH further bursting. With the impressive efficiency of GSH exhaustion and reactive oxygen species (ROS) storm generation, ferroptosis and apoptosis are significantly enhanced by FJP NCPs in vivo. In brief, this facile and efficient design for versatile nanoscale coordination polymers presents a novel paradigm for effectively elevating CDT efficiency and tumor synergistic therapy.

Self-amplified activatable nanoprodrugs for enhanced chemodynamic/chemo combination therapy

Chemodynamic therapy (CDT) has gained increasing attention by virtue of its high tumor specificity and low side effect. However, the low concentration of hydrogen peroxide (H2O2) in the tumor site suppresses the therapeutic efficacy of CDT. To improve the efficacy, introducing other kind of therapeutic modality is a feasible choice. Herein, we develop a self-amplified activatable nanomedicine (PCPTH NP) for chemodynamic/chemo combination therapy. PCPTH NP is composed of a H2O2-activatable amphiphilic prodrug PEG-PCPT and hemin. Upon addition of H2O2, the oxalate linkers within PCPTH NP are cleaved, which makes the simultaneous release of CPT and hemin. The released CPT can not only kill cancer cells but also upregulate the intracellular reactive oxygen species (ROS) level. The elevated ROS level may accelerate the release of drugs and enhance the CDT efficacy. PCPTH NP shows a H2O2 concentration dependent release profile, and can effectively catalyze H2O2 into hydroxyl radical (·OH) under acidic condition. Compared with PCPT NP without hemin, PCPTH NP has better anticancer efficacy both in vitro and in vivo with high biosafety. Thus, our study provides an effective approach to improve the CDT efficacy with high tumor specificity.

Homology-Activated Ultrasensitive Nanomedicines for Precise NIR-II FL/MRI Imaging-Guided "Knock-On" Dynamic Therapy in Rheumatoid Arthritis.

Stimuli-responsive nanomedicines represent a pivotal technology for in situ on-demand drug release and offer multiple advantages over conventional drug delivery systems to combat rheumatoid arthritis(RA). However, the lack of sensitivity to a single-stimuli source or the inability to synchronize multi-stimuli responses can easily lead to challenges in achieving precise-theranostics of RA. Herein, a homology-activated ultrasensitive nanomedicines MnO2-CQ4T-GOx(MCG NMs) is designed for NIR-II fluorescence(NIR-II FL)/magnetic resonance imaging(MRI)-guided effective "knock-on" dynamic anti-RA therapy. Building upon the characteristics of the RA-microenvironment, the MCG innovatively construct a MnO2-Mn2+ system, which can normalized activation sites. The ultrasensitive-responsive degradation is achieved using the multi-stimuli processes in the RA-microenvironment, triggering release of functional small molecules. The produced Mn2+ can exert Fenton-like activity to generate •OH from H2O2, thus providing the effective chemodynamic therapy(CDT). Moreover, the up-regulation of H2O2 by GOx-catalysis not only sensitizes the MnO2-Mn2+ system but also achieves self-enhancing CDT efficacy. The NIR-II FL quenching of CQ4T-BSA in the aggregated state occurs in MCG NMs, which can be rapidly and precisely "turn-on" via the MnO2-Mn2+ system. Meanwhile, the integration of activated Mn2+-based MRI imaging has successfully developed an activatable dual-modal imaging. Feedback imaging-guided precise photodynamic therapy of CQ4T-BSA can achieve efficient "knock-on" dynamic therapy for RA.

DNA Adjuvant Hydrogel-Optimized Enzymatic Cascade Reaction for Tumor Chemodynamic-Immunotherapy.

Chemodynamic therapy (CDT) shows immense potential in cancer treatment as it not only directly kills tumor cells but also induces anti-tumor immune responses. However, the efficacy of CDT is hampered by challenges in targeting CDT catalysts specifically to tumors using nanomaterials, along with the limitations of low H2 O2 levels and short catalyst duration within the tumor microenvironment. In this study, DNA adjuvant hydrogel to arrange a glucose oxidase-ferrocene cascade for continuously generating reactive oxygen species (ROS) from glucose in situ for tumor CDT combined with immunotherapy is employed. By precisely tuning the catalyst spacing with DNA double helix, ROS production efficiency is elevated by up to nine times compared to free catalysts, resulting in stronger immunogenetic cell death. Upon intratumoral injection, the DNA hydrogel system elicited potent anti-tumor immune responses, thereby effectively inhibiting established tumors and rejecting re-challenged tumors. This work offers a novel platform for integrated CDT and immunotherapy in cancer treatment.

Manganese self-boosting hollow nanoenzymes with glutathione depletion for synergistic cancer chemo-chemodynamic therapy.

Chemodynamic therapy (CDT) has outstanding potential as a combination therapy to treat cancer. However, the effectiveness of CDT in the treatment of solid tumors is limited by the overexpression of glutathione (GSH) in the tumor microenvironment (TME). GSH overexpression diminishes oxidative stress and attenuates chemotherapeutic drug-induced apoptosis in cancer cells. To counter these effects, a synergistic CDT/chemotherapy cancer treatment, involving the use of a multifunctional bioreactor of hollow manganese dioxide (HMnO2) loaded with cisplatin (CDDP), was developed. Metal nanoenzymes that can auto-degrade to produce Mn2+ exhibit Fenton-like, GSH-peroxidase-like activity, which effectively depletes GSH in the TME to attenuate the tumor antioxidant capacity. In an acidic environment, Mn2+ catalyzed the decomposition of intra-tumor H2O2 into highly toxic ·OH as a CDT. HMnO2 with large pores, pore volume, and surface area exhibited a high CDDP loading capacity (>0.6 g-1). Treatment with CDDP-loaded HMnO2 increased the intratumor Pt-DNA content, leading to the up-regulation of γ-H2Aχ and an increase in tumor tissue damage. The decreased GSH triggered by HMnO2 auto-degradation protected Mn2+-generated ·OH from scavenging to amplify oxidative stress and enhance the efficacy of CDT. The nanoenzymes with encapsulated chemotherapeutic agents deplete GSH and remodel the TME. Thus, tumor CDT/chemotherapy combination therapy is an effective therapeutic strategy.