Three Ru(II) complexes modulate the antioxidant transcription factor Nrf2 to overcome cisplatin resistance.

Here, we designed, synthesized and characterized three new cyclometalated Ru(II) complexes, [Ru(phen)2(1-(4-Ph-Ph)-IQ)]+ (phen = 1,10-phenanthroline, IQ = isoquinoline, RuIQ9), [Ru(phen)2(1-(4-Ph-Ph)-7-OCH3-IQ)]+ (RuIQ10), and [Ru(phen)2(1-(4-Ph-Ph)-6,7-(OCH3)2-IQ)]+ (RuIQ11). The cytotoxicity experiments conducted on both 2D and 3D multicellular tumor spheroids (MCTSs) indicated that complexes RuIQ9-11 exhibited notably higher cytotoxicity against A549 and A549/DDP cells when compared to the ligands and precursor compounds as well as clinical cisplatin. Moreover, the Ru(II) complexes displayed low toxicity when tested on normal HBE cells in vitro and exposed to zebrafish embryos in vivo. In addition, complexes RuIQ9-11 could inhibit A549 and A549/DDP cell migration and proliferation by causing cell cycle arrest, mitochondrial dysfunction, and elevating ROS levels to induce apoptosis in these cells. Mechanistic studies revealed that RuIQ9-11 could suppress the expression of Nrf2 and its downstream antioxidant protein HO-1 by inhibiting Nrf2 gene transcription in drug-resistant A549/DDP cells. Simultaneously, they inhibited the expression of efflux proteins MRP1 and p-gp in drug-resistant cells, ensuring the accumulation of the complexes within the cells. This led to an increase in intracellular ROS levels in drug-resistant cells, ultimately causing damage and cell death, thus overcoming cisplatin resistance. More importantly, RuIQ11 could effectively inhibit the migration and proliferation of drug-resistant cells within zebrafish, addressing the issue of cisplatin resistance. Accordingly, the prepared Ru(II) complexes possess significant potential for development as highly effective and low-toxicity lung cancer therapeutic agents to overcome cisplatin resistance.

Preparation, Characterization, and Antioxidant Properties of Self-Assembled Nanomicelles of Curcumin-Loaded Amphiphilic Modified Chitosan.

Curcumin (Cur) is a phytochemical with various beneficial properties, including antioxidant, anti-inflammatory, and anticancer activities. However, its hydrophobicity, poor bioavailability, and stability limit its application in many biological approaches. In this study, a novel amphiphilic chitosan wall material was synthesized. The process was carried out via grafting chitosan with succinic anhydride (SA) as a hydrophilic group and deoxycholic acid (DA) as a hydrophobic group; 1H-NMR, FTIR, and XRD were employed to characterize the amphiphilic chitosan (CS-SA-DA). Using a low-cost, inorganic solvent-based procedure, CS-SA-DA was self-assembled to load Cur nanomicelles. This amphiphilic polymer formed self-assembled micelles with a core-shell structure and a critical micelle concentration (CMC) of 0.093 mg·mL-1. Cur-loaded nanomicelles were prepared by self-assembly and characterized by the Nano Particle Size Potential Analyzer and transmission electron microscopy (TEM). The mean particle size of the spherical Cur-loaded micelles was 770 nm. The drug entrapment efficiency and loading capacities were up to 80.80 ± 0.99% and 19.02 ± 0.46%, respectively. The in vitro release profiles of curcumin from micelles showed a constant release of the active drug molecule. Cytotoxicity studies and toxicity tests for zebrafish exhibited the comparable efficacy and safety of this delivery system. Moreover, the results showed that the entrapment of curcumin in micelles improves its stability, antioxidant, and anti-inflammatory activity.

Cyclometalated ruthenium complexes overcome cisplatin resistance through PI3K/mTOR/Nrf2 signaling pathway.

Currently, cisplatin resistance remains a primary clinical obstacle in the successful treatment of non-small cell lung cancer. Here, we designed, synthesized, and characterized two novel cyclometalated Ru(II) complexes, [Ru(bpy)2(1-Ph-7-OCH3-IQ)] (PF6) (bpy = 2,2'-bipyridine, IQ = isoquinoline, RuIQ7)and [Ru(bpy)2(1-Ph-6,7-(OCH3)2-IQ)] (PF6) (RuIQ8). As experimental controls, we prepared complex [Ru(bpy)2(1-Ph-IQ)](PF6) (RuIQ6) lacking a methoxy group in the main ligand. Significantly, complexes RuIQ6-8 displayed higher in vitro cytotoxicity when compared to ligands, precursor cis-[Ru(bpy)2Cl2], and clinical cisplatin. Mechanistic investigations revealed that RuIQ6-8 could inhibit cell proliferation by downregulating the phosphorylation levels of Akt and mTOR proteins, consequently affecting the rapid growth of human lung adenocarcinoma cisplatin-resistant cells A549/DDP. Moreover, the results from qRT-PCR demonstrated that these complexes could directly suppress the transcription of the NF-E2-related factor 2 gene, leading to the inhibition of downstream multidrug resistance-associated protein 1 expression and effectively overcoming cisplatin resistance. Furthermore, the relationship between the chemical structures of these three complexes and their anticancer activity, ability to induce cell apoptosis, and their efficacy in overcoming cisplatin resistance has been thoroughly examined and discussed. Notably, the toxicity test conducted on zebrafish embryos indicated that the three Ru-IQ complexes displayed favorable safety profiles. Consequently, the potential of these developed compounds as innovative therapeutic agents for the efficient and low-toxic treatment of NSCLC appears highly promising.

A trispecific antibody induces potent tumor-directed T-cell activation and antitumor activity by CD3/CD28 co-engagement.

Aim: A novel CD19xCD3xCD28 trispecific antibody with a tandem single-chain variable fragments (scFv) structure was developed for the treatment of B-cell malignancies. Methods: The trispecific antibody in inducing tumor-directed T-cell activation and cytotoxicity was evaluated in vitro and in vivo and compared with its bispecific counterpart BiTE-CD19xCD3 lacking a CD28-targeting domain. Results: The trispecific antibody with a co-stimulatory domain exhibited augmented T-cell activation and memory T-cell differentiation capability and it induced faster tumor cell lysis than the bispecific antibody. RNAseq analysis revealed that the trispecific antibody modulates CD3/TCR complex-derived signal and upregulates antiapoptotic factors to influence the survival of T cells. Conclusion: By CD3/CD28 co-engagement, the trispecific antibody demonstrated its advantages in T-cell immunity and potential use as a more powerful and long-lasting T-cell engager.

T-cell based immunotherapies are a type of treatment that stimulates the body's own immune system to fight cancer. They have grown in popularity in recent years and have had impressive results in cancer treatment. One type of T-cell immunotherapy is a T-cell engager antibody. This is a type of molecule that redirects the body's immune cells to recognise and kill cancer cells. In this study, we developed a new type of T-cell engager antibody to treat two types of blood and bone marrow cancer. The antibody works by joining immune cells and cancer cells close together, to help activate the immune cells for cancer killing. This new type of T-cell engager antibody worked better than previous versions. It helped the immune cells survive longer and kill cancer more effectively. This means the new antibody might be better at treating people who have these types of cancers, but more testing in humans needs to be done.

Self-Assembled Amphiphilic Chitosan Nanomicelles: Synthesis, Characterization and Antibacterial Activity.

Although amphiphilic chitosan has been widely studied as a drug carrier for drug delivery, fewer studies have been conducted on the antimicrobial activity of amphiphilic chitosan. In this study, we successfully synthesized deoxycholic acid-modified chitosan (CS-DA) by grafting deoxycholic acid (DA) onto chitosan C2-NH2, followed by grafting succinic anhydride, to prepare a novel amphiphilic chitosan (CS-DA-SA). The substitution degree was 23.93% for deoxycholic acid and 29.25% for succinic anhydride. Both CS-DA and CS-DA-SA showed good blood compatibility. Notably, the synthesized CS-DA-SA can self-assemble to form nanomicelles at low concentrations in an aqueous environment. The results of CS, CS-DA, and CS-DA-SA against Escherichia coli and Staphylococcus aureus showed that CS-DA and CS-DA-SA exhibited stronger antimicrobial effects than CS. CS-DA-SA may exert its antimicrobial effect by disrupting cell membranes or forming a membrane on the cell surface. Overall, the novel CS-DA-SA biomaterials have a promising future in antibacterial therapy.

Mitochondria-targeted cyclometalated iridium (III) complexes: Dual induction of A549 cells apoptosis and autophagy.

In this study, we synthesized 4 cyclometalated iridium complexes using N-(1,10-phenanthrolin-5-yl)picolinamide (PPA) as the main ligand, denoted as [Ir(ppy)2PPA]PF6 (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)2PPA]PF6 (bzq = benzo[h]quinoline, Ir2), [Ir(dfppy)2PPA]PF6 (dfppy = 2-(3,5-difluorophenyl)pyridine, Ir3), and [Ir(thpy)2PPA]PF6 (thpy = 2-(thiophene-2-yl)pyridine, Ir4). Compared to cisplatin and oxaliplatin, all four complexes exhibited significant anti-tumor activity. Among them, Ir2 demonstrated higher cytotoxicity against A549 cells, with an IC50 value of 1.6 ± 0.2 µM. The experimental results indicated that Ir2 primarily localized in the mitochondria, inducing a large amount of reactive oxygen species (ROS) generation, that decreased in mitochondrial membrane potential (MMP), reduced ATP production, and further impaired mitochondrial function, leading to cytochrome c release. Additionally, Ir2 caused cell cycle arrest at the S phase and induced apoptosis through the AKT-mediated signaling pathway. Further investigations revealed that Ir2 could simultaneously induce both apoptosis and autophagy in A549 cells, with the latter acting as a non-protective mechanism that promoted cell death. More importantly, Ir2 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. Consequently, these newly developed Ir(III) complexes show great potential in the development of novel and low-toxicity anticancer agents.

A preliminary analysis of dental microstructure in Hamipterus (Pterosauria, Pterodactyloidea).

The toothed members of Pterosauria display an extremely wide range of tooth morphologies that supported a variety of feeding habits. Histological studies on the teeth of different pterosaur clades are potentially valuable in understanding the development of their tooth diversity. In this study, we used histological sections and scanning electron microscopy to describe and interpret the tooth microstructure of Hamipterus (Pterodactyloidea). Our analysis is based on seven teeth of Hamipterus (six isolated and one from a skull) from the Lower Cretaceous collected in Hami, China. Our results show that the enamel on the tooth crown is thin (~25 µm) in Hamipterus and covers only approximately half of the tooth crown. This thin enamel of the Hamipterus tooth makes it vulnerable and often becomes damaged during taphonomic and diagenetic processes. The radicular pulp inside the conical-shaped root shows a spindle space with a small foramen at the bottom, while the coronal pulp shows a small tunnel (100-140 µm in diameter). We estimate that the small teeth of Hamipterus likely took approximately 80 days to form. Furthermore, the tooth has Andresen lines, which represent 7-15 days period. For stable articulation of the tooth in the alveolus, the thick cellular cementum is concentrated on the lingual side of the root. The acellular cementum (~40 µm thick) layer runs from the root to the partial tooth crown.

Cyclometalated ruthenium (II) complexes induced HeLa cell apoptosis through intracellular reductive injury.

The main challenge of cancer chemotherapy is the resistance of tumor cells to oxidative damage. Herein, we proposed a novel antitumor strategy: cyclic metal­ruthenium (Ru) complexes mediate reductive damage to kill tumor cells. We designed and synthesized Ru(II) complexes with ß-carboline as ligands: [Ru (phen)2(NO2-Ph-ßC)](PF6) (RußC-7) and [Ru(phen)2(1-Ph-ßC)](PF6) (RußC-8). In vitro experimental results showed that RußC-7 and RußC-8 can inhibit cell proliferation, promote mitochondrial abnormalities, and induce DNA damage. Interestingly, RußC-7 with SOD activity could reduce intracellular reactive oxygen species (ROS) levels, while RußC-8 has the opposite effect. Accordingly, this study identified the reductive damage mechanism of tumor apoptosis, and may provide a new ideas for the design of novel metal complexes.

Nanozyme-based guanidinium peptides mediate surface reactive oxygen species for multidrug resistant bacterial infection management.

Nanozymes are effective novel antibacterial agents. However, they still have some shortcomings such as low catalytic efficiency, poor specificity, and non-negligible toxic side effects. Here, we synthesized iridium oxide nanozymes (IrOx NPs) by a one-pot hydrothermal method and used guanidinium peptide-betaine (SNLP/BS-12) to modify the surface of IrOx NPs (SBI NPs) to obtain a high-efficiency and low-toxicity antibacterial agent. In vitro experiments showed that SBI NPs with SNLP/BS12 could enhance IrOx NPs to target bacteria, mediate bacterial surface catalysis and reduce the cytotoxicity of IrOx NPs to mammalian cells. Importantly, SBI NPs were able to effectively alleviate MRSA acute lung infection and effectively promote diabetic wound healing. Accordingly, iridium oxide nanozymes functionalized with guanidinium peptides are expected to be an effective antibiotic candidate in the postantibiotic era.

Ir(IV) and Ir(III) in situ transition promotes ROS generation for eradicating multidrug-resistant bacterial infection.

Whether reactive oxygen species are a consequence or a cause of antibacterial activity is not fully known. A glutathione (GSH)-mediated oxidative defense mechanism is an important factor against bacterial infection. Reactive oxygen species (ROS) storm-mediated bacterial death by depleting GSH is also considered an effective strategy. Therefore, we designed and synthesized hybrid iridium ruthenium oxide nanozymes (IrRuOx NPs), where IrRuOx NPs alternately consume GSH through double redox electron pair auto-valent cycles, while an IrRuOx NP-mediated Fenton-like reaction occurs to realize an ROS storm, which in turn mediates lipid peroxidation to promote bacterial death. The results showed that IrRuOx NPs can effectively inhibit and kill Gram-positive and Gram-negative bacteria in vitro, and can be used as broad-spectrum antibiotics. Importantly, the wound and sepsis models of MRSA infection confirmed the efficient antibacterial activity of IrRuOx NPs in vivo. Accordingly, this study provides a new idea for metal oxide hybrid nanoenzymes and their biological functions.

Reactive oxygen species-mediated CuRuOX@HA hybrid nanozymes for multidrug-resistant bacterial infections with synergistic photothermal therapy.

Drug-resistant bacterial infections pose a serious threat to human life and health, especially multidrug-resistant bacterial infections are difficult to treat with currently available antibiotics. A number of evidences showed that reactive oxygen species (ROS) and photothermal therapy (PTT) can easily kill drug-resistant bacteria while they have not developed resistance to drugs. Inspired by good stability and high catalytic activity of nanozymes and in order to construct versatile nanozymes, the therapy of ROS was integrated with PTT. This study prepared a ROS-mediated copper-ruthenium oxide (CuRuOX) hybrid nanozyme (CuRuOX@HA) modified with hyaluronic acid (HA). Via hybridization, CuRuOX@HA NPs not only have good ROS generation capability but also possess excellent photothermal performance with a photothermal conversion efficiency of 62.7%. Thus, the CuRuOX@HA nanozyme achieves the synergistic treatment of drug-resistant bacterial infections using PTT/chemodynamic therapy (CDT). Moreover, under the mediated action of ROS, CuRuOX@HA can effectively deplete glutathione, which is a nutrient of bacteria, and hence, the nanozyme can impede the growth of drug-resistant bacteria. In vivo, this hybrid nanozyme efficiently removes MRSA from infected wounds and speeds up wound healing with few adverse effects. The CuRuOX@HA hybrid nanozyme is a viable candidate for clinical treatment due to its strong antibacterial activities and good biosafety.

Ruthenium(II) complexes as mitochondrial inhibitors of topoisomerase induced A549 cell apoptosis.

Two new ruthenium(II) complexes [Ru(dip)2(PPßC)]PF6 (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)2(PPßC)]PF6 (Ru2, phen = 1, 10-phenanthroline) with ß-carboline derivative PPßC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC50 values ranging from 0.5 to 3.6 µM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.

Mitochondria-targeted cyclometalated iridium-ß-carboline complexes as potent non-small cell lung cancer therapeutic agents.

Natural products and metals play a crucial role in cancer research and the development of antitumor drugs. We designed and synthesized three new carboline-based cyclometalated iridium complexes [Ir(C-N)2(PPßC)](PF6), where PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide, C-N = 2-phenylpyridine (ppy, Ir1), 2-(2,4-difluorophenyl) pyridine (dfppy, Ir2), 7,8-benzoquinoline (bzq, Ir3), by combining iridium with ß-carboline derivative. These iridium complexes exhibited high potential antitumor effects after being promptly taken up by A549 cells. Accumulating in mitochondria rapidly and preferentially, Ir1-3 caused a series of changes in mitochondrial events, including the loss of mitochondrial membrane potential, the depletion of cellular ATP, and the elevation of reactive oxygen species, leading to significant death of A549 cells. Moreover, the activation of intracellular caspase pathway and apoptosis was further validated to contribute to iridium complexes-induced cytotoxicity. These novel iridium complexes exerted a prominent inhibitory effect on tumor growth in a three-dimensional multicellular tumor spheroid model.

Macrophage Polarization Induced by Bacteria-Responsive Antibiotic-Loaded Nanozymes for Multidrug Resistance-Bacterial Infections Management.

Inherited bacterial resistance and biofilm-induced local immune inactivation are important factors in the failure of antibiotics to fight against bacterial infections. Herein, antibiotic-loaded mesoporous nanozymes (HA@MRuO2 -Cip/GOx) are fabricated for overcoming bacterial resistance, and activating the local immunosuppression in biofilm microenvironment (BME). HA@MRuO2 -Cip/GOx are prepared by physical adsorption between ciprofloxacin (Cip) or glucose oxidase (GOx) and MRuO2 NPs, and modified with hyaluronic acid (HA). In vitro, HA@MRuO2 -Cip/GOx cleaves extracellular DNA (eDNA) to disrupt biofilm, thereby enhancing Cip kill planktonic bacteria. Furthermore, HA@MRuO2 -Cip/GOx can induce polarization and enhance phagocytosis of a macrophage-derived cell line. More importantly, in vivo therapeutic performance confirms that HA@MRuO2 -Cip/GOx can trigger macrophage-related immunity, and effectively alleviate MRSA-bacterial lung infections. Accordingly, nanocatalytic therapy combined with targeted delivery of antibiotics could enhance the treatment of bacterial infections.

Silkworm spinning inspired 3D printing toward a high strength scaffold for bone regeneration.

Inspired by the silkworm spinning process for production of tough cocoons, a gradient printing-assembly technique with silk fibroin (SF) and hydroxyapatite (HA) to achieve high strength scaffolds for bone regeneration is developed. A coaxial extrude-nozzle is employed to provide gathered thickening and shearing for aligned assembly. The aligned SF-HA assembles into the compacted nanostructure, which performs a maximum compressive strength of 166 MPa and bending strength of 40 MPa. Scaffolds with various morphologies could be arbitrarily constructed via extruded 3D printing for the regeneration of cortical bone or cancellous bone. The hemolysis quantification of red blood cells (RBCs), proliferation and flow cytometry of bone marrow stem cells (BMSCs) have proved the excellent biocompatibility of the printed scaffolds. Osteogenic induced differentiation assay in vitro and surgical intervention for rat femoral defect repairing have verified the successful osteogenesis with high mechanical strength and remarkable stability in the physiological environment. The silkworm spinning inspired 3D printing offers a facile approach for the fabrication of implantable scaffolds with high strength and excellent biocompatibility, which is highly desired for the applications of bone tissue engineering.

Low dinosaur biodiversity in central China 2 million years prior to the end-Cretaceous mass extinction.

Whether or not nonavian dinosaur biodiversity declined prior to the end-Cretaceous mass extinction remains controversial as the result of sampling biases in the fossil record, differences in the analytical approaches used, and the rarity of high-precision geochronological dating of dinosaur fossils. Using magnetostratigraphy, cyclostratigraphy, and biostratigraphy, we establish a high-resolution geochronological framework for the fossil-rich Late Cretaceous sedimentary sequence in the Shanyang Basin of central China. We have found only three dinosaurian eggshell taxa (Macroolithus yaotunensis, Elongatoolithus elongatus, and Stromatoolithus pinglingensis) representing two clades (Oviraptoridae and Hadrosauridae) in sediments deposited between ∼68.2 and ∼66.4 million y ago, indicating sustained low dinosaur biodiversity, and that assessment is consistent with the known skeletal remains in the Shanyang and surrounding basins of central China. Along with the dinosaur eggshell records from eastern and southern China, we find a decline in dinosaur biodiversity from the Campanian to the Maastrichtian. Our results support a long-term decline in global dinosaur biodiversity prior to 66 million y ago, which likely set the stage for the end-Cretaceous nonavian dinosaur mass extinction.

A neutrophil cell membrane-biomimetic nanoplatform based on L-arginine nanoparticles for early osteoarthritis diagnosis and nitric oxide therapy.

Osteoarthritis (OA) is a common debilitating disease affecting articular joints for which no effective disease-modifying early diagnosis or medical therapy tools are currently available. The inefficient delivery of drugs into inflamed chondrocytes has restricted the development of anti-OA medication. Evidence has shown that inflammatory neutrophils possess the property of targeting inflammation via inflammatory tissue recruiting. Herein, we report neutrophil-cell-membrane-based biomimetic nanoparticles (NM-LANPs@Ru) as an OA theranostic nanoplatform; they act as a NO delivery system, coating neutrophil cell membrane onto the surface of self-assembled PEGylated L-arginine nanoparticles (LANPs) to act as a NO donor and loading a Ru complex to act as a ROS inducer. NM-LANPs@Ru demonstrated the specific targeting of inflamed OA with low toxicity, good NO release, and excellent fluorescence/photoacoustic (FL/PA) imaging properties. We showed that NM-LANPs@Ru exhibited enhanced cellular association in inflamed chondrocyte cells (C28/I2), much higher than NO release from ROS oxidized LA, and it improved the inhibition of the apoptosis of inflamed C28/I2 cells compared with control treatments. In vivo studies demonstrated that NM-LANPs@Ru effectively targeted inflamed OA, based on real-time dual-modal FL/PA imaging, eventually exhibiting its excellent anti-inflammatory activity. Our study may provide a new approach for the early diagnosis and treatment of osteoarthritis using a neutrophil-cell-membrane-based biomimetic nanoplatform for NO or drug delivery.

Iridium oxide nanoparticles mediated enhanced photodynamic therapy combined with photothermal therapy in the treatment of breast cancer.

Photodynamic therapy (PDT) of tumor has achieved good results, but the treatment efficiency is not high due to the lack of effective photosensitizers and tumor hypoxia. In this study, iridium dioxide nanoparticles (IrO2 NPs) with excellent photothermal/photodynamic effects and catalase like activity were synthesized by a simple method. The combination of glucose oxidase (GOx) and IrO2 NPs is formed by hyaluronic acid (HA), which have the activities of glucose oxidase and catalase, can target tumor sites and form in situ amplifiers in tumor microenvironment (IrO2-GOx@HA NPs). Firstly, GOx convert the high levels of glucose in the tumor to hydrogen peroxide (H2O2), and then IrO2 NPs convert H2O2 to oxygen (O2), which can enhance the type II of PDT. IrO2 NPs also can be used as a thermosensitive agent for photothermal therapy (PTT). In cancer cells, IrO2-GOx@HA NPs-mediated amplifier enhances the effect of type II of PDT, aggravating the apoptosis of breast cancer (4T1) cells and cooperating with its own PTT to further improve the overall treatment effect. Under simulated hypoxic conditions of tumor tissue, it was found that IrO2-GOx@HA NPs treatment can effectively relieve hypoxia inside tumor tissue. In addition, the results in vivo further proved that, IrO2-GOx@HA NPs can enhance the role of II PDT and cooperate with PTT to treat breast cancer effectively. The results highlight the prospect of IrO2-GOx@HA NPs in controlling and regulating tumor hypoxia to overcome the limitations of current cancer therapy.

A ruthenium nanoframe/enzyme composite system as a self-activating cascade agent for the treatment of bacterial infections.

The cascade catalytic strategy could effectively enhance the antibacterial activity by regulating the production of hydroxyl radicals (˙OH) in the sites of bacterial infection. In this work, a ruthenium metal nanoframe (Ru NF) was successfully synthesized via the palladium template method. The cascade catalysis in the bacterial infection microenvironment was achieved by physically adsorbed natural glucose oxidase (GOx), and hyaluronic acid (HA) was coated on the outer layer of the system for locating the infection sites accurately. Eventually, a composite nano-catalyst (HA-Ru NFs/GOx) based on the ruthenium nanoframe was constructed, which exhibited excellent cascade catalytic activity and good biocompatibility. The prepared HA-Ru NFs/GOx enhances the antibacterial activity and inhibits bacterial regeneration through the outbreak of reactive oxygen species (ROS) caused by self-activating cascade reactions. In addition, in vivo experiments indicate that HA-Ru NFs/GOx could efficiently cause bacterial death and significantly promote wound healing/skin regeneration. Accordingly, ruthenium metal framework nanozymes could be used as an effective cascade catalytic platform to inhibit bacterial regeneration and promote wound healing, and have great potential as new antibacterial agents against antibiotic-resistant bacteria.

Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans.

The contents of numerous membrane lipids change upon ageing. However, it is unknown whether and how any of these changes are causally linked to lifespan regulation. Acyl chains contribute to the functional specificity of membrane lipids. In this study, working with C. elegans, we identified an acyl chain-specific sphingolipid, C22 glucosylceramide, as a longevity metabolite. Germline deficiency, a conserved lifespan-extending paradigm, induces somatic expression of the fatty acid elongase ELO-3, and behenic acid (22:0) generated by ELO-3 is incorporated into glucosylceramide for lifespan regulation. Mechanistically, C22 glucosylceramide is required for the membrane localization of clathrin, a protein that regulates membrane budding. The reduction in C22 glucosylceramide impairs the clathrin-dependent autophagic lysosome reformation, which subsequently leads to TOR activation and longevity suppression. These findings reveal a mechanistic link between membrane lipids and ageing and suggest a model of lifespan regulation by fatty acid-mediated membrane configuration.