Toxic Reactive Oxygen Species Research Articles

Local glycolysis-modulating hydrogel microspheres for a combined anti-tumor and anti-metastasis strategy through metabolic trapping strategy.

Anti-glycolysis is well-recognized for inhibition of tumor proliferation. However, tumor metabolic heterogeneity confers great challenges in the therapeutic efficacy of glycolysis inhibitors. Here, a metabolic trapping strategy was employed to avoid metabolism heterogeneity in tumors. Unlike usual glycolysis inhibition, the glycolysis level was first promoted. Then excessive metabolite of lactate was transformed into H2O2 and hydroxyl radical by lactate oxidase (LOX) and MIL-101 (Fe) nanoparticles (MF). Finally, the ATP production was inhibited, and the tumor was suppressed by the generation of toxic reactive oxygen species (ROS). We realized this strategy via methacrylated gelatin (GelMA) hydrogel microspheres, co-loaded with metformin (MET) and LOX@MF. The results showed that MET was completely released within 2h, followed by most LOX@MF released within 72h. LOX@MF and MET synergistically suppressed tumor proliferation and angiogenesis both in vitro and in vivo. Compared with control, the primary tumor volume was reduced by 75.7%, and the average number of lung metastasis nodules decreased from 15.5 to 1.0. Regarding the metabolism, higher glycolytic enzymes expressions were observed initially, followed by lower lactate and vascular endothelial growth factor (VEGF), and finally elevated ROS levels. Overall, our study provides new insights to improve metabolism heterogeneity-limited metabolic cancer therapy.

Rational Design of Nanozymes for Engineered Cascade Catalytic Cancer Therapy.

Nanozymes have shown significant potential in cancer catalytic therapy by strategically catalyzing tumor-associated substances and metabolites into toxic reactive oxygen species (ROS) in situ, thereby inducing oxidative stress and promoting cancer cell death. However, within the complex tumor microenvironment (TME), the rational design of nanozymes and factors like activity, reaction substrates, and the TME itself significantly influence the efficiency of ROS generation. To address these limitations, recent research has focused on exploring the factors that affect activity and developing nanozyme-based cascade catalytic systems, which can trigger two or more cascade catalytic processes within tumors, thereby producing more therapeutic substances and achieving efficient and stable cancer therapy with minimal side effects. This area has shown remarkable progress. This Perspective provides a comprehensive overview of nanozymes, covering their classification and fundamentals. The regulation of nanozyme activity and efficient strategies of rational design are discussed in detail. Furthermore, representative paradigms for the successful construction of cascade catalytic systems for cancer treatment are summarized with a focus on revealing the underlying catalytic mechanisms. Finally, we address the current challenges and future prospects for the development of nanozyme-based cascade catalytic systems in biomedical applications.

A novel Sai-based antioxidant agent attenuates antibody-mediated rejection in allogeneic rat kidney transplantation.

Antibody-mediated rejection (ABMR) remains a leading cause of graft loss during kidney transplantation. Ischemia reperfusion injury (IRI) has been reported to promote T-cell proliferation, leading to B-cell activation and subsequent production of donor-specific antibodies (DSA), which target antigens on the vascular endothelium. We hypothesize that a novel therapeutic strategy targeting highly toxic reactive oxygen species could mitigate oxidative stress and immune responses associated with IRI. Our previous study demonstrated that oral administration of a silicon (Si)-based agent consistently generates substantial amounts of hydrogen, effectively suppressing IRI-induced oxidative stress and acute kidney injury in a rat renal clamp model. Here, we investigated the effect of the Si-based agent on immune responses in an allogeneic kidney transplant setting. Using both short-term and long-term evaluation models, we found that the Si-based agent suppressed oxidative stress and acquired immunity activation. Furthermore, early suppression of DSA production and amelioration of chronic ABMR were observed. These findings indicate that the Si-based agent offers protective effects on graft function and survival, highlighting its potential clinical application to improve outcomes for kidney transplant recipients.

Oxidative Stress Early After Hematopoietic Stem Cell Transplant.

HSCT conditioning regimens cause massive lysis of hematopoietic cells with release of toxic intracellular molecules into the circulation. To describe the response to oxidative stress early after hemopoietic stem cell transplantation (HSCT) and assess the association of early oxidative stress with later transplant outcomes. Key components of in the body's physiological response to oxidative stress were studied in a cohort of 122 consecutive pediatric allogeneic HSCT recipients. Glutathione reductase (GSR), glutathione peroxidase (GPX) and glutathione synthetase protein expression was measured using ELISA and reduced and oxidized glutathione (GSH and GSSG) levels were quantified using mass spectrometry. GSR is an inducible enzyme which catalyzes the regeneration of reduced glutathione (GSH). Levels of GSR increased by more than five-fold between start of conditioning chemotherapy and day 0 (median 87ng/mL to 459ng/mL, p<0.0001). GPX catalyzes removal of toxic reactive oxygen species (ROS) by oxidation of GSH. GPX4 levels fell briskly by day 0 (median 20.3 ng/mL prior to HSCT to 7.4ng/mL at day 0, p<0.0001), likely indicating consumption of the enzyme as cell lysis and subsequent oxidative stress occurred. Levels of the antioxidant substrate reduced glutathione stayed stable from pre-HSCT through day 14, likely maintained by increased glutathione synthesis by the enzyme glutathione synthetase, whose median levels increased from 38.8ng/mL before conditioning to 54ng/mL at day 21 (p=0.02). GSR levels were associated with patient outcomes. Median GSR levels were significantly elevated through days 0-21 in those who died in the first year after HSCT compared to those who survived. Similarly, patients who developed high risk transplant-associated thrombotic microangiopathy (TA-TMA) and grade 2 and above graft vs host disease (GVHD) also had significantly higher GSR levels early after HSCT. Our data suggest that the body is for the most part able to mount a brisk and effective response to the oxidative stress associated with lysis of the hematopoietic cell system before HSCT. Our data also suggest that early events in the first 21 days of HSCT may set the scene for later clinical events in the first year after HSCT. It is plausible that patients who are unable to effectively overcome this early period of significant oxidative stress may have increased endothelial injury and activation of complement. Potential therapeutics to augment and optimize the body's response to oxidative stress may improve outcomes.

EFFECT OF ORAL TRIPEPTIDE-COLLAGEN ON MICROCIRCULATION (NAIL FOLDS) AND SKIN WRINKLES

Background: Accelerated aging is associated with increased exposure to reactive oxygen species (ROS), leading to lower collagen and elastin levels in the body. This reduction reduces microvascular activity, causing microcirculatory disorders and skin wrinkles. Administering collagen tripeptides can help improve the microcirculation system. Objective: This study aims to investigate the effects of collagen tripeptide on improving microcirculation, reducing skin wrinkles, and lowering excessive ROS toxicity. Method: The research method used is experimental with a pre-post study approach without using a control group and descriptive quantitative data analysis. We measured microcirculation using a microscope, quantified ROS levels with the QYM-DI microscope, and assessed nasolabial fold depth with an acupuncture needle. Results: The study results indicate that collagen tripeptide significantly improves microcirculation, reduces skin wrinkles, and decreases excessive ROS toxicity. The non-parametric Wilcoxon test results are as follows: (1) there is a significant difference before and after collagen tripeptide consumption in terms of microcirculation improvement (p = 0.000), reduction of skin wrinkles on the nasolabial folds (p = 0.008), and reduction of ROS (p = 0.000). This improves microcirculation, which in turn reduces skin wrinkles on the nasolabial folds. Conclusion: Consuming collagen tripeptide for three months can improve microcirculation, reduce skin wrinkles on the nasolabial folds, and reduces ROS.

Nanogenerators Supplying Highly Toxic Reactive Oxygen Species for Antitumor Therapy and Immune Activation

Nanogenerators Supplying Highly Toxic Reactive Oxygen Species for Antitumor Therapy and Immune Activation

Hierarchical Targeting Nanodrug with Holistic DNA Protection for Effective Treatment of Acute Kidney Injury.

Acute kidney injury (AKI) manifests a hallmark pathological feature of extensive and severe DNA damage in renal tubules, primarily induced by the excessive of toxic reactive oxygen species (ROS) from the mitochondrial electron transport chain. The kidney's complex intricate physiological architecture and the heterogeneous intracellular environment pose significant challenges for effective sequential and high-resolution drug delivery-an urgent issue that remains unresolved. To address this, a hierarchical-targeting antioxidant nanodrug has been developed with a folic acid moiety (HAND) designed for high-resolution drug delivery in AKI treatment. For the first time, HAND enables sequential targeting from the kidney to the most severely damaged proximal tubular epithelial cells (PTECs), ultimately concentrating in the DNA-rich mitochondria and nucleus. As a result, HAND effectively scavenges ROS in situ, protecting both mitochondria and nuclei along with their vital genetic material. This action restores mitochondrial function, mitigates DNA oxidation and fragmentation, reduces apoptosis, and inhibits cGAS/STING-mediated sterile inflammation. Consequently, HAND demonstrates remarkable efficacy in safeguarding injured kidneys during AKI. Overall, this work pioneers a hierarchical, high-resolution antioxidant strategy, providing innovative guidance for the development of AKI therapies.

Sonoactivated Z-Scheme Heterojunction for Enhanced Sonodynamic Mitophagy Inhibition and Triple Negative Breast Cancer Treatment.

Sonodynamic therapy (SDT) has emerged as a potent therapeutic modality to generate intratumoral toxic reactive oxygen species (ROS) in combating refractory triple-negative breast cancer (TNBC). However, its therapeutic efficacy is compromised due to pro-survival cancer-cell mitophagy to mitigate mitochondrial oxidative damage. Here, an "all-in-one" tumor-therapeutic strategy that integrates nanosonosensitizer-augmented noninvasive SDT with mitophagy inhibition is reported. This is achieved using a rationally constructed sonoactivated liquid Z-scheme heterojunction that connects sonosensitizer PtCu3 nanocages and mitophagy-blocking sonosensitizer BP nanosheets via an amphipathic organic linker (PEI-PEG5000-C18). The conjugated electron mediator (M, Cp*Rh(phen)Cl) is strategically positioned between the 2 sonosensitizers to facilitate electron transfer. This M-based Z-scheme configuration prolongs the separation of sonoactivated electron-hole pairs, leading to efficient ROS generation upon ultrasound stimulation. Importantly, Cu2+ released from PtCu3 expedites BP degradation by reducing phosphorus vacancy formation energy, improving the overall biodegradability of BP-M-PtCu3 and favoring phosphate ions production. These ions elevate lysosomal pH, inhibiting the hydrolysis of damaged mitochondria within autophagic lysosomes, thus preventing cancer cell self-preservation under oxidative stress and effectively eliminating TNBC. It is believe that the M-based sonoactivated Z-scheme heterojunction will be a promising sonosensitizer structure, and the sonodynamic mitophagy inhibition strategy offers valuable prospects for cancer treatment.

A fluorescence probe for monitoring toxic hypochlorous acid in biosystems and environmental waters with a broad pH adaptation

Hypochlorous acid (HOCl) is commonly utilized in various daily applications. As a toxic reactive oxygen species (ROS) that generated from the industrial and pharmaceutical aspects, it plays a critical role in the mass cycle of environmental system and various biological processes. Understanding the complicated roles of HOCl in environment and biosystems requires the development of precise and efficient detection methods. Thus, in this work, a novel fluorescent probe, MQ-ClO, has been designed to detect hypochlorous acid by utilizing hypochlorous acid-triggered oxidative intramolecular cyclization. This probe exhibits rapid and sensitive response, with a detection limit as low as 35 nM. More importantly, the probe is capable of functioning under highly acidic or basic conditions, exhibiting a wide pH range adaptability from pH 2–11. Furthermore, MQ-ClO has been effectively used to detect HOCl in real water samples. Besides, the low toxicity of MQ-ClO enables its practical application in monitoring endogenous/exogenous HOCl levels in living cells as well as zebrafish.

Nanozymes as Antibacterial Agents: New Concerns in Design and Enhancement Strategies.

Nanozymes exhibiting natural enzyme-mimicking catalytic activities as antibacterial agents present several advantages, including high stability, low cost, broad-spectrum antibacterial activity, ease of preparation and storage, and minimal bacterial resistance. Consequently, they have attracted significant attention in recent years. However, the rapid expansion of antimicrobial nanozyme research has resulted in pioneering reviews that do not comprehensively address emerging concerns and enhancement strategies within this field. This paper first summarizes the factors influencing the intrinsic activity of nanozymes; subsequently, we outline new research considerations for designing antibacterial nanozymes with enhanced functionality and biosafety features such as degradable, imageable, targeted, and bacterial-binding nanozymes as well as those capable of selectively targeting pathogenic bacteria while sparing normal cells and probiotics. Furthermore, we review novel enhancement strategies involving external physical stimuli (light or ultrasound), the introduction of extrinsic small molecules, and self-supplying H2O2 to enhance the activity of antibacterial nanozymes under physiological conditions characterized by low concentrations of H2O2 and O2. Additionally, we present non-redox nanozymes that operate independently of highly toxic reactive oxygen species (ROS) alongside those designed to combat less common pathogenic bacteria. Finally, we discuss current issues, challenges faced in the field, and future prospects for antibacterial nanozymes.

Synthesis, Characterization and Antibacterial Activity Evaluation of CuO NPs and B-CuO NPs Obtained from Livistona Chinensis Leaf Extract.

Nanoparticles (NPs) exhibit fascinating size-dependent chemical and physical characteristics that make them useful for a variety of applications. The present paper reports the green synthesis of CuO NPs and B-doped CuO NPs (B-CuO NPs) from Livistona chinensis leaf extract. Not much work has been reported on the use of the plant extract for the fabrication of NPs, particularly those of Cu and its doped counterparts. Various spectroscopic techniques were used to characterize the synthesized NPs. In the FT-IR spectra, peaks obtained at 504 cm-1 to 600 cm-1 were due to Cu-O vibrations. The energy dispersive X-ray analysis (EDX) spectra confirmed the CuO NPs' composition and B's presence inside the NPs. The peak pattern in the X-ray diffraction (XRD) spectrum confirmed the crystalline and monoclinic phases of the NPs. The average crystalline size of CuO NPs and B-CuO NPs was 19.56 nm and 17.30 nm respectively. The CuO and B-CuO NPs were tested against three Gram-positive bacterial strains namely Bacillus subtilis, Micrococcus luteus, and Staphylococcus aureus and three Gram-negative Escherichia coli, Salmonella abony, and Pseudomonas aeruginosa through Agar well diffusion method and it was found that CuO NPs showed higher activity than B-CuO NPs. Gentamicin was used as the positive control. The antibacterial activity may be due to the cell wall disruption by induction of innate and adaptive host immune response, generating toxic reactive oxygen species (ROS), and stimulating intracellular effects.

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.

Reactive Oxygen Detoxification Contributes to Mycobacterium abscessus Antibiotic Survival.

When a population of bacteria encounter a bactericidal antibiotic most cells die rapidly. However, a sub-population, known as "persister cells", can survive for prolonged periods in a non-growing, but viable, state. Persister cell frequency is dramatically increased by stresses such as nutrient deprivation, but it is unclear what pathways are required to maintain viability, and how this process is regulated. To identify the genetic determinants of antibiotic persistence in mycobacteria, we carried out transposon mutagenesis high-throughput sequencing (Tn-Seq) screens in Mycobacterium abscessus (Mabs). This analysis identified genes essential in both spontaneous and stress-induced persister cells, allowing the first genetic comparison of these states in mycobacteria, and unexpectedly identified multiple genes involved in the detoxification of reactive oxygen species (ROS). We found that endogenous ROS were generated following antibiotic exposure, and that the KatG catalase-peroxidase contributed to survival in both spontaneous and starvation-induced persisters. We also found that that hypoxia significantly impaired bacterial killing, and notably, in the absence of oxygen, KatG became dispensable. Thus, the lethality of some antibiotics is amplified by toxic ROS accumulation, and persister cells depend on detoxification systems to remain viable.

Autophagy Blockage Enhancing Photothermal and Chemodynamic Synergistic Therapy Based on HCQ/CuS Nanoplatform.

As an intracellular protective mechanism, autophagy has the potential to significantly impair the therapeutic effects of photothermal therapy (PTT) and chemodynamic therapy (CDT), which helps cancer cells survive under harsh conditions, such as high temperature and reactive oxygen species (ROS). In this study, an autophagy blockage enhanced PTT and CDT synergistic therapy nanoplatform is constructed by loading hydroxychloroquine (HCQ) with autophagy inhibitory effect into hollow copper sulfide (HCuS). Specifically, HCuS produces toxic ROS through Fenton-like reaction in the tumor microenvironment (TME). At the same time, PTT-mediated temperature elevation of the tumor region accelerates the Fenton-like reaction and ROS production, enhancing the therapeutic effect of CDT. Furthermore, the internal autophagy inhibitor HCQ significantly blocks the fusion of autophagosomes and lysosomes by deacidifying lysosomes, cutting off the self-protection mechanism of cancer cells, and amplifying the combined treatment of PTT and CDT. Both in vitro and in vivo results demonstrate that the combination of photothermal-enhanced chemodynamic therapy with inhibition of autophagy provides new insights into designing multifunctional therapeutic nanoagents.

Hyaluronic acid modified Cu/Mn-doped metal-organic framework nanocatalyst for chemodynamic therapy

Chemodynamic therapy (CDT) is a new method for cancer treatment that produces highly toxic reactive oxygen species (ROS) in the tumor microenvironment to induce cancer cell apoptosis or necrosis. However, the therapeutic effect of CDT is often hindered by intracellular H2O2deficiency and the activity of antioxidants such as glutathione (GSH). In this study, a nano-catalyst HCM was developed using a self-assembled Cu/Mn-doped metal-organic framework, and its surface was modified with hyaluronic acid to construct a tumor-targeting CDT therapeutic agent with improved the efficiency and specificity. Three substances HHTP (2, 3, 6, 7, 10, 11-hexahydroxybenzophenanthrene), Cu2+, and Mn2+were shown to be decomposed and released under weakly acidic conditions in tumor cells. HHTP produces exogenous H2O2in the presence of oxygen to increase the H2O2content in tumors, Cu2+reduces GSH content and generates Cu+in the tumor, and Cu+and Mn2+catalyze H2O2to produce ∙OH in a Fenton-like reaction. Together, these three factors change the tumor microenvironment and improve the efficiency of ROS production. HCM showed selective and efficient cytotoxicity to cancer cells, and could effectively inhibit tumor growthin vivo, indicating a good CDT effect.

Light-chilling Stress Causes Hyper-accumulation of Iron in Shoot, Exacerbating Leaf Oxidative Damage in Cucumber.

Iron availability within the root system of plants fluctuates depending on various soil factors, which directly impacts plant growth. Simultaneously, various environmental stressors, such as high/low temperatures and high light intensity, affect plant photosynthesis in the leaves. However, the combined effects of iron nutrient conditions and abiotic stresses have not yet been clarified. In this study, we analyzed how iron nutrition conditions impact the chilling-induced damage on cucumber leaves (Cucumis sativus L.). When cucumbers were grown under different iron conditions and then exposed to chilling stress, plants grown under a high iron condition exhibited more severe chilling-induced damage than the control plants. Conversely, plants grown under a low-iron condition showed an alleviation of the chilling-induced damages. These differences were observed in a light-dependent manner, indicating that iron intensified the toxicity of reactive oxygen species generated by photosynthetic electron transport. In fact, plants grown under the low-iron condition showed less accumulation of malondialdehyde derived from lipid peroxidation after chilling stress. Notably, the plants grown under the high iron condition displayed a significant accumulation of iron and an increase in lipid peroxidation in the shoot, specifically after light-chilling stress, but not after dark-chilling stress. This indicated that increased root-to-shoot iron translocation, driven by light and low temperature, exacerbated leaf oxidative damage during chilling stress. These findings also highlight the importance of managing iron nutrition in the face of chilling stress and will facilitate crop breeding and cultivation strategies.

Photothermal and enhanced chemodynamic reinforced anti-tumor therapy based on PDA@POM nanocomposites

Chemodynamic therapy (CDT) and photothermal therapy (PTT) have both demonstrated considerable efficacy in the tumor treatment individually, owing to their non-invasive nature and excellent selectivity. However, due to the propensity of tumors for metastasis and recurrence, a singular therapeutic approach falls short of achieving optimal treatment outcomes. Polydopamine (PDA) has excellent photothermal conversion ability and polyoxometalates (POMs) possess diverse enzymatic activities. Here, we synthesized PDA@POM nanospheres comprising polydopamine-coated Tungsten-based polyoxometalate (W-POM). These nanospheres leverage dual enzymatic activities that synergistically enhance both chemodynamic and photothermal therapies for tumor treatment. The PDA-mediated PTT effect enables precise tumor cell destruction, while the W-POM nanozymes catalyzes the generation of highly toxic reactive oxygen species (ROS) from hydrogen peroxide within tumor cells through a Fenton-like reaction, which mitigates tumor hypoxia and induces tumor cell death. This synergistic photothermal catalytic therapy shows enhanced efficacy in tumor suppression, providing a promising new approach for tumor treatment.

Rationally designed catalytic nanoplatform for enhanced chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment

Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment.Graphical abstract

Ultrasmall Enzyodynamic PANoptosis Nano-Inducers for Ultrasound-Amplified Hepatocellular Carcinoma Therapy and Lung Metastasis Inhibition.

Addressing the inefficiency of current therapeutic approaches for hepatocellular carcinoma is an urgent and pressing challenge. PANoptosis, a form of inflammatory programmed cell death, presents a dependable strategy for combating cancer by engaging multiple cell death pathways (apoptosis, pyroptosis, and necroptosis). In this study, an ultrasmall Bi2Sn2O7 nanozyme with ultrasound-magnified multienzyme-mimicking properties is designed and engineered as a PANoptosis inducer through destroying the mitochondrial function of tumor cells and enhancing the intracellular accumulation of toxic reactive oxygen species, finally triggering the activation of PANoptosis process. The role of PANoptosis inducer has been verified by the expression of related proteins, including cleaved Caspase 3, NLRP3, N-GSDMD, cleaved Caspase 1, p-MLKL, and RIPK3. The inclusion of external ultrasonic irradiation significantly augments the enzyodynamic therapeutic efficiency. In vitro and in vivo antineoplastic efficacy, along with inhibition of lung metastasis, validate the benefits of the Bi2Sn2O7-mediated PANoptosis pathway. This study not only elucidates the intricate mechanisms underlying Bi2Sn2O7 as a PANoptosis inducer, but also offers a novel perspective for the treatment of hepatocellular carcinoma.

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.