The effects of repeated freezing and thawing on bovine sperm morphometry and function.

Refreezing the remaining genetic resources after in vitro fertilization (IVF) can conserve genetic materials. However, the precise damage inflicted by repeated freezing and thawing on bovine sperm and its underlying mechanism remain largely unexplored. Thus, this study investigates the impact of repeated freeze-thaw cycles on sperm. Our findings indicate that such cycles significantly reduce sperm viability and motility. Furthermore, the integrity of the sperm plasma membrane and acrosome is compromised during this process, exacerbating the advanced apoptosis triggered by oxidative stress. Additionally, transmission electron microscopy exposed severe damage to the plasma membranes of both the sperm head and tail. Notably, the "9 + 2" structure of the tail was disrupted, along with a significant decrease in the level of the axonemal protein DNAH10, leading to reduced sperm motility. IVF outcomes revealed that repeated freeze-thaw cycles considerably impair sperm fertilization capability, ultimately reducing the blastocyst rate. In summary, our research demonstrates that repeated freeze-thaw cycles lead to a decline in sperm viability and motility, attributed to oxidative stress-induced apoptosis and DNAH10-related dynamic deficiency. As a result, the utility of semen is compromised after repeated freezing.

Anti-Freezing and Ultrasensitive Zwitterionic Betaine Hydrogel-Based Strain Sensor for Motion Monitoring and Human-Machine Interaction.

Ultrasensitive and reliable conductive hydrogels are significant in the construction of human-machine twinning systems. However, in extremely cold environments, freezing severely limits the application of hydrogel-based sensors. Herein, building on biomimetics, a zwitterionic hydrogel was elaborated for human-machine interaction employing multichemical bonding synergies and experimental signal analyses. The covalent bonds, hydrogen bonds, and electrostatic interactions construct a dense double network structure favorable for stress dispersion and hydrogen bond regeneration. In particular, zwitterions and ionic conductors maintained excellent strain response (99 ms) and electrical sensitivity (gauge factor = 14.52) in the dense hydrogel structure while immobilizing water molecules to enhance the weather resistance (-68 °C). Inspired by the high sensitivity, zwitterionic hydrogel-based strain sensors and remote-control gloves were designed by analyzing the experimental signals, demonstrating promising potential applications within specialized flexible materials and human-machine symbiotic systems.

Recent advances in the development and applications of luminescent bacteria-based biosensors.

Luminescent bacteria-based biosensors are widely used for fast and sensitive monitoring of food safety, water quality, and other environmental pollutions. Recent advancements in biomedical engineering technology have led to improved portability, integration, and intelligence of these biotoxicity assays. Moreover, genetic engineering has played a significant role in the development of recombinant luminescent bacterial biosensors, enhancing both detection accuracy and sensitivity. This review provides an overview of recent advances in the development and applications of novel luminescent bacteria-based biosensors, and future perspectives and challenges in the cutting-edge research, market translation, and practical applications of luminescent bacterial biosensing are discussed.

Defect-Engineered Tin Disulfide Nanocarriers as "Precision-Guided Projectile" for Intensive Synergistic Therapy.

Nanoformulations with endogenous/exogenous stimulus-responsive characteristics show great potential in tumor cell elimination with minimal adverse effects and high precision. Herein, an intelligent nanotheranostic platform (denoted as TPZ@Cu-SnS2-x /PLL) for tumor microenvironment (TME) and near-infrared light (NIR) activated tumor-specific therapy is constructed. Copper (Cu) doping and the resulting sulfur vacancies can not only improve the response range of visible light but also improve the separation efficiency of photogenerated carriers and increase the carrier density, resulting in the ideal photothermal and photodynamic performance. Density functional theory calculations revealed that the introduction of Cu and resulting sulfur vacancies can induce electron redistribution, achieving favorable photogenerated electrons. After entering cells through endocytosis, the TPZ@Cu-SnS2-x /PLL nanocomposites show the pH responsivity property for the release of the TPZ selectively within the acidic TME, and the released Cu2+ can first interact with local glutathione (GSH) to deplete GSH with the production of Cu+ . Subsequently, the Cu+ -mediated Fenton-like reaction can decompose local hydrogen peroxide into hydroxyl radicals, which can also be promoted by hyperthermia derived from the photothermal effect for tumor cell apoptosis. The integration of photoacoustic/computed tomography imaging-guided NIR phototherapy, TPZ-induced chemotherapy, and GSH-elimination/hyperthermia enhanced chemodynamic therapy results in synergistic therapeutic outcomes without obvious systemic toxicity in vivo.

Microbial responses and changes in metabolic products in bovine uteri infected with Staphylococcus aureus.

There is mounting evidence that the uterine microbiota has an important role in the pathogenesis of endometritis, with invasion of pathogenic bacteria being a main cause of uterine microbial imbalance. However, mechanisms of uterine microbiota resistance to pathogen invasion remain unclear. In this study, an intrauterine infusion of Staphylococcus aureus was used as a bovine endometritis model; it significantly increased abundance of pathogenic bacteria (Streptococcus, Helccoccus, Fusobacterium, and Escherichia-Shigella) and significantly decreased abundance of probiotics (Allstipes, Bacteroides, Phascolarctobacterium, Romboutsia, and Prevotella). In addition, the metabolite aloe-emodin was positively correlated with Prevotella and based on combined analyses of omics and probiotics, the presence of its metabolite aloe-emodin in the uterus at least partially resisted Staphylococcus aureus invasion. Therefore, Aloe-emodin has potential for regulating microbial structure and preventing endometritis.

Higher incidence of meibomian gland dysfunction in postmenopausal women with primary acquired nasolacrimal duct obstruction.

PURPOSE: This study aimed to investigate the incidence of meibomian gland dysfunction (MGD) in postmenopausal women with primary acquired nasolacrimal duct obstruction (PANDO) and enables ophthalmologists to pay attention to ocular surface damage before surgery. METHODS: 165 postmenopausal women with PANDO and 115 postmenopausal women with a normal lacrimal drainage system were enrolled in this prospective study. Based on the results of lacrimal duct irrigation and age, the participants were further subdivided. The incidence of different severities of MGD in different groups was calculated and analyzed by the chi-squared test. RESULTS: The incidence of MGD in the PANDO group was 81.21%, and in the control group, it was 46.96%, which was significantly higher in the presence of PANDO (p < 0.001). The incidence of severe MGD in the complete and incomplete PANDO groups was higher than that in the control group (all p < 0.05), and no significant differences were observed between the complete and incomplete PANDO groups. The incidence of moderate MGD was significantly higher in the complete PANDO group than in the control group (p < 0.001). When age was considered an independent variable, the results revealed a significant value for patients aged < 70 years (p < 0.001). CONCLUSIONS: Our study revealed a prodominantly high incidence of MGD in postmenopausal women with PANDO, especially in a complete PANDO or aged < 70 years. Ophthalmologists need to pay close attention to MGD in postmenopausal women with PANDO.

Three-Step Depletion Strategy of Glutathione: Tunable Metal-Organic-Framework-Engineered Nanozymes for Driving Oxidative/Nitrative Stress to Maximize Ferroptosis Therapy.

Ferroptosis is a novel type of nonapoptotic programmed cell death involving the accumulation of lipid peroxidation (LPO) to a lethal threshold. Herein, we propose tunable zeolitic imidazolate framework (ZIFs)-engineered biodegradable nanozymes for ferroptosis mediated by both reactive oxygen species (ROS) and nitrogen species (RNS). l-Arginine is utilized as an exogenous nitric oxide donor and loaded into hollow ZIFs@MnO2 artificial nanozymes, which are formed by etching ZIFs with potassium permanganate and simultaneously generating a MnO2 shell in situ. The constructed nanozymes with multienzyme-like activities including peroxidase, oxidase, and catalase can release satisfactory ROS and RNS through a cascade reaction, consequently promoting the accumulation of LPO. Furthermore, it can improve the efficiency of ferroptosis through a three-step strategy of glutathione (GSH) depletion; that is, the outer MnO2 layer consumes GSH under slightly acidic conditions and RNS downregulates SLC7A11 and glutathione reductase, thus directly inhibiting GSH biosynthesis and indirectly preventing GSH regeneration.

Recurrence of macular edema in patients with branch retinal vein occlusion: a proteomic study.

BACKGROUND: Branch retinal vein occlusion (BRVO) is a common retinal vascular disease leading to severe vision loss and blindness. This study aimed to investigate and reveal the pathophysiological mechanisms underlying macular edema (ME) recurrence in patients with BRVO through a proteomic approach. METHODS: We detected proteins in the aqueous humor of 14 untreated, four refractory, and four post-operative patients with BRVO-ME and 12 age-matched cataract controls using four-dimensional label-free proteomic and bioinformatics analyses. RESULTS: In total, 84 proteins exhibited significant differential expression between the BRVO and control samples (fold change [FC] ≥ 1.2 and adjusted p-value < 0.05). Compared to the control group, 43 and 41 proteins were upregulated and downregulated, respectively, in the BRVO group. These proteins were involved in cell adhesion, visual perception, retina homeostasis, and platelet activation. Several significantly enriched signaling pathways included complement and coagulation cascades and platelet activation. In the protein-protein interaction networks generated using the search tool for retrieval of interacting genes (STRING), the fibrinogen alpha chain and fibrinogen beta chain constituted a tightly connected cluster. Many common protein expression trends, such as the fibrinogen alpha chain and fibrinogen beta chain, were observed in both the recurrent and refractory groups. Differentially expressed proteins in the two groups were involved in complement activation, acute-phase response, platelet activation, and platelet aggregation. Important signaling pathways include the complement and coagulation cascades, and platelet activation. Protein-protein interaction analysis suggested that the fibrinogen alpha chain and fibrinogen beta chain constituted a tightly connected cluster. The expression of some differentially expressed proteins shared by the BRVO and the recurrent and refractory groups was reversed in the post-operative group. CONCLUSIONS: Our study is the first to analyze the proteomics of recurrent, refractory, and post-operative groups treated for BRVO-ME, and may potentially provide novel therapeutic interventions for the recurrence of ME.

Oxygen-Vacancy-Engineered W18 O49-x Nanobrush with a Suitable Band Structure for Highly Efficient Sonodynamic Therapy.

With the rapid development of external minimally invasive or noninvasive therapeutic modalities, ultrasound-based sonodynamic therapy (SDT) is a new alternative for treating deep tumors. However, inadequate sonosensitizer efficiency and poor biosecurity limit clinical applications. In this study, we prepared an oxygen-vacancy-engineered W18 O49-x nanobrush with a band gap of 2.79 eV for highly efficient SDT using a simple solvothermal method. The suitable band structures of the W18 O49-x nanobrush endows it with the potential to simultaneously produce singlet oxygen (1 O2 ), superoxide anions (⋅O2 - ), and hydroxyl radicals (⋅OH) under ultrasound irradiation. Additionally, abundant oxygen vacancies that serve as further charge traps that inhibit electron-hole recombination are incidentally introduced through one-step thermal reduction. Collectively, the in vitro and in vivo results demonstrate that the oxygen-vacancy-engineered W18 O49-x nanobrush delivers highly efficient reactive oxygen species (ROS) for SDT in a very biosafe manner. Overall, this study provides a new avenue for discovering and designing inorganic nanosonosensitizers with enhanced therapeutic efficiencies for use in SDT.

Architecture of Vanadium-Based MXene Dysregulating Tumor Redox Homeostasis for Amplified Nanozyme Catalytic/Photothermal Therapy.

Taking the significance of the special microenvironment for tumor cell survival into account, disrupting tumor redox homeostasis is highly prospective for improving therapeutic efficacy. Herein, a multifunctional 2D vanadium-based MXene nanoplatform, V4 C3 /atovaquone@bovine albumin (V4 C3 /ATO@BSA, abbreviated as VAB) has been elaborately constructed for ATO-enhanced nanozyme catalytic/photothermal therapy. The redox homeostasis within the tumor cells is eventually disrupted, showing a remarkable anti-tumor effect. The VAB nanoplatform with mixed vanadium valence states can induce a cascade of catalyzed reactions in the tumor microenvironment, generating plenty of reactive oxygen species (ROS) with effective glutathione consumption to amplify oxidative stress. Meanwhile, the stable and strong photothermal effect of VAB under near-infrared irradiation not only causes the necrosis of tumor cells, but also improves its peroxidase-like activity. In addition, the release of ATO can effectively alleviate endogenous oxygen consumption to limit triphosadenine formation and inhibit mitochondrial respiration. As a result, the expression of heat shock proteins is effectively suppressed to overcome thermoresistance and the production of ROS can be further promoted due to mitochondrial injury. Moreover, VAB also presents high photoacoustic and photothermal imaging performances. In brief, the multifunctional nanoplatform can provide ATO-enhanced nanozyme catalytic/photothermal therapy with broadening the biomedical applications of vanadium-based MXene.

A bubble-enhanced lanthanide-doped up/down-conversion platform with tumor microenvironment response for dual-modal photoacoustic and near-infrared-II fluorescence imaging.

As an important tumor diagnosis strategy in precision medicine, multimodal imaging has been widely studied. However, the weak imaging signal with low spatial resolution and the constant signal of lack of specific activation severely limit its disease diagnosis. Herein, a bubble-enhanced lanthanide-based up/down-conversion platform with tumor microenvironment response for dual-mode imaging, LDNP@DMSN-Au@CaCO3 nanoparticles (named as LDAC NPs) were successfully developed. Combining the advantages of photoacoustic imaging (PAI) and the second near-infrared window (NIR-II) fluorescence imaging (FI), significantly improved the accuracy of diseases diagnosis. LDAC NPs with flower-like structure were synthesized through the encapsulation of uniform lanthanide-doped nanoparticles (NaYbF4:Ce,Er@NaYF4 named LDNPs) with dendritic mesoporous silica (DMSN). The gold nanoparticles (Au NPs) were then in situ grown on the surface of DMSN and the surface were finally coated with a layer of calcium carbonate (CaCO3). Under the excitation of the 980 nm laser, LDNPs showed strong emission of NIR-II at 1550 nm due to the doping of Ce and Er ions, showcasing excellent spatial resolution and deep tissue penetration characteristics, while the resulting visible light emission (540 nm) enables Au NPs to generate PAI signals with the aid of LDNPs via the fluorescence resonance energy transfer effect. In acidic tumoral environment, CaCO3 layer could produce CO2 microbubbles, and the PAI signals of LDAC NPs could be further enhanced with the generation of CO2 bubbles due to the bubble cavitation effect. Simultaneously, the NIR-II FI of LDAC NPs was self-enhanced with the degradation of the CaCO3. This intelligent nanoparticle with stimulus-activated dual-mode imaging capability holds great promise in future precision diagnostics.

Melatonin Inhibits Testosterone Synthesis in Rooster Leydig Cells by Targeting CXCL14 through miR-7481-3p.

Melatonin has been proved to be involved in testosterone synthesis, but whether melatonin participates in testosterone synthesis by regulating miRNA in Leydig cells is still unclear. The purpose of this study is to clarify the mechanism of melatonin on Leydig cells testosterone synthesis from the perspective of miRNA. Our results showed that melatonin could significantly inhibit testosterone synthesis in rooster Leydig cells. miR-7481-3p and CXCL14 were selected as the target of melatonin based on RNA-seq and miRNA sequencing. The results of dual-luciferase reporter assays showed that miR-7481-3p targeted the 3'-UTR of CXCL14. The overexpression of miR-7481-3p significantly inhibited the expression of CXCL14 and restored the inhibitory role of melatonin testosterone synthesis and the expression of StAR, CYP11A1, and 3ß-HSD in rooster Leydig cells. Similarly, interference with CXCL14 could reverse the inhibitory effect of melatonin on the level of testosterone synthesis and the expression of StAR, CYP11A1, and 3ß-HSD in rooster Leydig cells. The RNA-seq results showed that melatonin could activate the PI3K/AKT signal pathway. Interference with CXCL14 significantly inhibited the phosphorylation level of PI3K and AKT, and the inhibited PI3K/AKT signal pathway could reverse the inhibitory effect of CXCL14 on testosterone synthesis and the expression of StAR, CYP11A1 and 3ß-HSD in rooster Leydig cells. Our results indicated that melatonin inhibits testosterone synthesis by targeting miR-7481-3p/CXCL14 and inhibiting the PI3K/AKT pathway.

Deep Insight of Design, Mechanism, and Cancer Theranostic Strategy of Nanozymes.

Since the discovery of enzyme-like activity of Fe3O4 nanoparticles in 2007, nanozymes are becoming the promising substitutes for natural enzymes due to their advantages of high catalytic activity, low cost, mild reaction conditions, good stability, and suitable for large-scale production. Recently, with the cross fusion of nanomedicine and nanocatalysis, nanozyme-based theranostic strategies attract great attention, since the enzymatic reactions can be triggered in the tumor microenvironment to achieve good curative effect with substrate specificity and low side effects. Thus, various nanozymes have been developed and used for tumor therapy. In this review, more than 270 research articles are discussed systematically to present progress in the past five years. First, the discovery and development of nanozymes are summarized. Second, classification and catalytic mechanism of nanozymes are discussed. Third, activity prediction and rational design of nanozymes are focused by highlighting the methods of density functional theory, machine learning, biomimetic and chemical design. Then, synergistic theranostic strategy of nanozymes are introduced. Finally, current challenges and future prospects of nanozymes used for tumor theranostic are outlined, including selectivity, biosafety, repeatability and stability, in-depth catalytic mechanism, predicting and evaluating activities.

Modulation of macrophage polarization by iron-based nanoparticles.

Macrophage polarization is an essential process involved in immune regulation. In response to different microenvironmental stimulation, macrophages polarize into cells with different phenotypes and functions, most typically M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages. Iron-based nanoparticles have been widely explored and reported to regulate macrophage polarization for various biomedical applications. However, the influence factors and modulation mechanisms behind are complicated and not clear. In this review, we systemically summarized different iron-based nanoparticles that regulate macrophage polarization and function and discussed the influence factors and mechanisms underlying the modulation process. This review aims to deepen the understanding of the modulation of macrophage polarization by iron-based nanoparticles and expects to provide evidence and guidance for subsequent design and application of iron-based nanoparticles with specific macrophage modulation functions.

Magnetic Delivery of Antigen-Loaded Magnetic Liposomes for Active Lymph Node Targeting and Enhanced Anti-Tumor Immunity.

Therapeutic cancer vaccines offer the greatest advantage of enhancing antigen-specific immunity against tumors, particularly for immunogenic tumors, such as melanoma. However, clinical responses remain unsatisfactory, primarily due to inadequate T cell priming and the development of acquired immune tolerance. A major obstacle lies in the inefficient uptake of antigen by peripheral dendritic cells (DCs) and their migration to lymph nodes for antigen presentation. In this context, the magnetic delivery of antigen-loaded magnetic liposomes (Ag-MLs) to actively target lymph node, is proposed. These magnetic responsive liposomes contain soluble mouse melanoma lysate and iron oxide nanoparticles in the core, along with the immunostimulatory adjuvant CpG-1826 incorporated into the lipid bilayer. When applied through magnetic targeting in the mouse melanoma model, Ag-MLs accumulate significantly in the target lymph nodes. This accumulation results in increased population of active DCs in lymph nodes and cytotoxic T lymphocytes (CTLs) within tumors, correlating with effective tumor growth inhibition. Overall, this study demonstrates the potential of magnetic targeting as an effective strategy for delivering cancer vaccines and activating the immune response, offering a novel platform for cancer immunotherapies.

Melatonin Attenuates Oxidative Stress-Induced Apoptosis of Bovine Ovarian Granulosa Cells by Promoting Mitophagy via SIRT1/FoxO1 Signaling Pathway.

Oxidative-stress-induced apoptosis of granulosa cells is considered to be a main driver of follicular atresia. Increasing evidence suggests a protective effect of melatonin against oxidative damage but the mechanism remains unclear. The aim of this study is to investigate the effects of melatonin on mitophagy and apoptosis of bovine ovarian granulosa cells under oxidative stress, and to clarify the mechanism. Our results indicate that melatonin inhibited H2O2-induced apoptosis and mitochondrial injury of bovine ovarian granulosa cells, as revealed by decreased apoptosis rate, reactive oxygen species (ROS) levels, Ca2+ concentration, and cytochrome C release and increased mitochondrial membrane potential (ΔΨm). Simultaneously, melatonin promoted mitophagy of bovine ovarian granulosa cells through increasing the expression of PTEN-induced putative kinase 1 (PINK1), PARKIN, BECLIN1, and LC3II/LC3I; decreasing the expression of sequestosome 1 (SQSMT1); and promoting mitophagosome and lysosome fusion. After treatment with a mitophagy inhibitor CsA, we found that melatonin alleviated apoptosis and mitochondrial injury through promoting mitophagy in bovine ovarian granulosa cells. Furthermore, melatonin promoted the expression of silent information regulator 1 (SIRT1) and decreased the expression level of forkhead transcription factors class O (type1) (FoxO1). By treatment with an SIRT1 inhibitor EX527 or FoxO1 overexpression, the promotion of melatonin on mitophagy as well as the inhibition on mitochondrial injury and apoptosis were reversed in bovine ovarian granulosa cells. In conclusion, our results suggest that melatonin could promote mitophagy to attenuate oxidative-stress-induced apoptosis and mitochondrial injury of bovine ovarian granulosa cells via the SIRT1/FoxO1 signaling pathway.

Potential use of garlic products in ruminant feeding: A review.

The addition of antibiotics as growth promoters to ruminant feed can result in bacterial resistance and antibiotic residues in ruminant products. Correspondingly, there is serious public concern regarding the presence of antibiotic residue in ruminant products and the consequent threat to human health. As a result, the addition of plants and their products to ruminant feeds, as an alternative to antibiotics, has received much attention recently. Garlic and its products are rich in organosulphur compounds, which have a variety of biological activities and have been widely used as natural additives in animal production. This review presents recent knowledge on the addition of garlic products (powder, skin, oil, leaf and extracts) to the diets of ruminants. In this paper, garlic products are evaluated with respect to their chemical composition, bioactive compounds, and their impacts on the rumen ecosystem, antioxidant status, immune response, parasitic infection, growth performance and product quality of ruminants. This review provides valuable guidance and a theoretical basis for the development of garlic products as green, highly efficient and safe additives, with the aims of promoting ruminant growth and health, reducing methane emissions and improving ruminant product quality. Garlic extracts have the potential to control parasite infections by decreasing the faecal egg count. Garlic powder, oil and allicin are able to reduce the methane emissions of ruminants. Organosulphur compounds such as allicin, which is present in garlic products, have the potential to inhibit membrane lipid synthesis of the archaeal community, thus influencing the population of methanogenic archaea and resulting in a reduction in methane emissions. Some garlic products are also able to increase the average daily gain (garlic skin, water extract, and leaf) and the feed conversion ratio (garlic skin and leaf) of ruminants. Garlic stalk silage fed to sheep has the potential to improve the nutritional value of mutton by increasing the concentrations of linoleic and linolenic acids and essential amino acids. Sheep fed a diet containing garlic powder or oil are able to produce milk with higher concentrations of the conjugated linoleic acids and n-3 fatty acids, which has health benefits for consumers, due to the widely recognized positive impact of n-3 polyunsaturated fatty acids and conjugated linoleic acids on human heart health, improving platelet aggregation, vasodilation and thrombotic tendency. Overall, garlic products have the potential to enhance growth performance and product quality and reduce parasite infections, as well as methane emissions of ruminants.

Biomineralized RuO2 Nanozyme with Multi-Enzyme Activity for Ultrasound-Triggered Peroxynitrite-Boosted Ferroptosis.

Ferroptosis, as a non-apoptotic cell death pathway, has attracted increasing attention for cancer therapy. However, the clinical application of ferroptosis-participated modalities is severely limited by the low efficiency owing to the intrinsic intracellular regulation pathways. Herein, chlorin e6 (Ce6) and N-acetyl-l-cysteine-conjugated bovine serum albumin-ruthenium dioxide is elaborately designed and constructed for ultrasound-triggered peroxynitrite-mediated ferroptosis. Upon ultrasound stimulation, the sonosensitizers of Ce6 and RuO2 exhibit highly efficient singlet oxygen (1 O2 ) generation capacity, which is sequentially amplified by superoxide dismutase and catalase-mimicking activity of RuO2 with hypoxia relief. Meanwhile, the S-nitrosothiol group in BCNR breaks off to release nitric oxide (NO) on-demand, which then reacts with 1 O2 forming highly cytotoxic peroxynitrite (ONOO- ) spontaneously. Importantly, BCNR nanozyme with glutathione peroxidase-mimicking activity can consume glutathione (GSH), along with the generated ONOO- downregulates glutathione reductase, avoiding GSH regeneration. The two-parallel approach ensures complete depletion of GSH within the tumor, resulting in the boosted ferroptosis sensitization of cancer cells. Thus, this work presents a superior paradigm for designing peroxynitrite-boosted ferroptosis sensitization cancer therapeutic.

Multiple therapeutic mechanisms of pyrrolic N-rich g-C3N4 nanosheets with enzyme-like function in the tumor microenvironment.

Nanozyme-based synergistic catalytic therapies for tumors have attracted extensive research attention. However, the unsatisfactory efficiency and negative impact of the tumor microenvironment (TME) hinder its clinical applications. In this study, we provide an easy method to prepare transition metals loaded onto pyrrolic nitrogen-rich g-C3N4 (PN-g-C3N4) for forming metal-N4 sites. This N-rich material effectively transfers electrons from g-C3N4 to metal-N4 sites, promotes the oxidation-reduction reaction of metals with different valence states, and improves material reusability. Under TME conditions, copper ions loaded onto PN-g-C3N4 (Cu-PN-g-C3N4, CPC) can produce ·OH through a Fenton-like reaction for tumor inhibition. This Fenton-like reaction and tumor cell inhibition can be improved further by a photodynamic effect caused by light irradiation. We introduced upconversion nanoparticles (UCNPs) into CPC to obtain nano-enzymes (UCNPs@Cu-PN-g-C3N4, UCPC) for effectively penetrating the tissue, which emits light corresponding to the UV absorption region of CPC when excited with 980 nm near-infrared (NIR) light. The nanoplatform can reduce H2O2 concentration upon exposure to NIR light; this induces an increase in dissolved oxygen content and produces a higher supply of reactive oxygen species (ROS) for destroying tumor cells. Owing to the narrow bandgap (1.92 eV) of UCPC under 980 light irradiation, even under the condition of hypoxia, the excited electrons in the conduction band can reduce insoluble O2 through a single electron transfer process, thus effectively generating O2•-. Nanoenzyme materials with catalase properties produce three types of ROS (·OH, O2•- and 1O2) when realizing chemodynamic and photodynamic therapies. An excellent therapeutic effect was established by killing cells in vitro and the tumor-inhibiting effect in vivo, proving that the prepared nanoenzymes have an effective therapeutic effect and that the endogenous synergistic treatment of multiple treatment technologies can be realized.

Sm/Co-Doped Silica-Based Nanozymes Reprogram Tumor Microenvironment for ATP-Inhibited Tumor Therapy.

Current applications of multifunctional nanozymes for reprogramming the redox homeostasis of the tumor microenvironment (TME) have been severely confronted with low catalytic activity and the ambiguity of active sites of nanozymes, as well as the stress resistance from the rigorous physical environment of tumor cells. Herein, the Sm/Co-doped mesoporous silica with 3PO-loaded nanozymes (denoted as mSC-3PO) are rationally constructed for simultaneously inhibiting energy production by adenosine triphosphate (ATP) inhibitor 3PO and reprogramming TME by multiactivities of nanozymes with photothermal effect assist, i.e., enhanced peroxidase-like, catalase-like activity, and glutathione peroxidase-like activities, facilitating reactive oxygen species (ROS) generation, promoting oxygen content, and restraining the over-expressed glutathione. Through the optimal regulation of nanometric size and doping ratio, the fabricated superparamagnetic mSC-3PO enables the excellent exposure of active sites and avoids agglomeration owing to the large specific surface and mesoporous structure, thus providing adequate Sm/Co-doped active sites and enough spatial distribution. The constructed Sm/Co centers both participate in the simulated biological enzyme reactions and carry out the double-center catalytic process (Sm3+ and Co3+ /Co2+ ). Significantly, as the inhibitor of glycolysis, 3PO can reduce the ATP flow by cutting down the energy transform, thereby inhibiting tumor angiogenesis and assisting ROS to promote the early withering of tumor cells. In addition, the considerable near-infrared (NIR) light absorption of mSC-3PO can adapt to NIR excitable photothermal treatment therapy and photoexcitation-promoted enzymatic reactions. Taken together, this work presents a typical therapeutic paradigm of multifunctional nanozymes that simultaneously reprograms TME and promotes tumor cell apoptosis with photothermal assistance.