Targeting ONECUT2 inhibits tumor angiogenesis via down-regulating ZKSCAN3/VEGFA.

OC-2 plays a vital role in tumor growth, metastasis and angiogenesis, but molecular mechanism how OC-2 regulates angiogenic factors is unclear. We found that OC-2 was highly expressed in HepG2, COLO, MCF-7, SKOV3 cells and rectum carcinoma tissues, and angiogenic factors levels were positively related to OC-2. Then OC-2 KD inhibited the tumor growth, metastasis and angiogenesis process in vitro and vivo. ChIP-Seq showed that 228 target genes of OC-2 were identified and they were associated with tumor growth, metastasis, angiogenesis and signal transduction; OC-2 bound to ZKSCAN3 at promoter region. Luciferase assays showed that ZKSCAN3 was identified as target gene of OC-2 and VEGFA was identified as target gene of ZKSCAN3; OC-2 promoted VEGFA expression via activating ZKSCAN3 transcriptional program. Importantly, OC-2 KD down-regulated VEGFA secretion to suppress tumor angiogenesis of HUVECs. Besides VEGFA, OC-2 was positively correlated with other angiogenic factors HIF-1α, FGF2, EGFL6 and HGF. Meanwhile, ERK1/2 and Smad1 signaling pathways might be related to function of OC-2 driving tumor aggressiveness. We revealed that OC-2 might regulate tumor growth, metastasis, angiogenesis via ERK1/2, Smad1 signaling pathways and regulate VEGFA expression for tumor angiogenesis via activating ZKSCAN3 transcriptional program, indicating that OC-2 was a convincing target to develop novel anti-tumor drugs based on angiogenesis.

Effects of micro- and nano-plastics on growth, antioxidant system, DMS, and DMSP production in Emiliania huxleyi.

Due to the potential impacts of microplastics (MPs) and nanoplastics (NPs) on algal growth and thereby affect the climate-relevant substances, dimethylsulfoniopropionate (DMSP) and dimethyl sulfide (DMS), we studied the polystyrene (PS) MPs and NPs of 1 µm and 80 nm impacts on the growth, chlorophyll content, reactive oxygen species (ROS), antioxidant enzyme activity, and DMS/DMSP production in Emiliania huxleyi. E. huxleyi is a prominent oceanic alga that plays a key role in DMS and DMSP production. The results revealed that high concentrations of MPs and NPs inhibited the growth, carotenoid (Car), and Chl a concentrations of E. huxleyi. However, short-time exposure to low concentrations of PS MPs and NPs stimulated the growth of E. huxleyi. Furthermore, high concentrations of MPs and NPs resulted in an increase in the superoxide anion radical (O2.-) production rate and a decrease in the malondialdehyde (MDA) content compared with the low concentrations. Exposure to MPs and NPs at 5 mg L-1 induced superoxide dismutase (SOD) activity as a response to scavenging ROS. High concentrations of MPs and NPs significantly inhibited the production of DMSP and DMS. The findings of this study support the potential ecotoxicological impacts of MPs and NPs on algal growth, antioxidant system, and dimethylated sulfur compounds production, which maybe potentially impact the global climate.

Influence of the community assemblage on sulfur distributions in the South China sea.

Marine distribution of dimethylsulfoniopropionate (DMSP) and its cleavage product dimethyl sulfide (DMS) is greatly affected by the community structures of bacteria, phytoplankton, and zooplankton. Spatial distributions of dissolved and particulate DMSP (DMSPd,p), and DMS were measured and their relationships with DMSP lyase activity (DLA), abundance of DMSP-consuming bacteria (DCB), and the community structures of phytoplankton, zooplankton, and bacteria were determined during summer in the South China Sea (SCS). The depth distributions of DMSPd,p exhibited a similar trend with Chl a, reaching their maxima in the mixing layer. The DMS concentration was positively correlated with DCB abundance and DLA, indicating that DCB and DMSP lyase had a significant effect on DMS production. High DMS concentrations in the horizontal distribution coincided with high DCB abundance and DLA and may be due to the rapid growth of phytoplankton resulting from the high dissolved inorganic nitrogen concentration brought by the cold vortices. Moreover, the highest copepod abundance at station G3 coincided with the highest DMS concentrations there among stations B4, F2, and G3. These results suggest that copepod may play an important role in DMS production. The bacterial SAR11 clade was positively correlated with DLA, indicating its significant contribution to DMSP degradation in the SCS. These findings contribute to the understanding of the effect of the community assemblage on DMSP/DMS distributions in the SCS dominated by mesoscale vortices.

Silicon-containing nanomedicine and biomaterials: materials chemistry, multi-dimensional design, and biomedical application.

The invention of silica-based bioactive glass in the late 1960s has sparked significant interest in exploring a wide range of silicon-containing biomaterials from the macroscale to the nanoscale. Over the past few decades, these biomaterials have been extensively explored for their potential in diverse biomedical applications, considering their remarkable bioactivity, excellent biocompatibility, facile surface functionalization, controllable synthesis, etc. However, to expedite the clinical translation and the unexpected utilization of silicon-composed nanomedicine and biomaterials, it is highly desirable to achieve a thorough comprehension of their characteristics and biological effects from an overall perspective. In this review, we provide a comprehensive discussion on the state-of-the-art progress of silicon-composed biomaterials, including their classification, characteristics, fabrication methods, and versatile biomedical applications. Additionally, we highlight the multi-dimensional design of both pure and hybrid silicon-composed nanomedicine and biomaterials and their intrinsic biological effects and interactions with biological systems. Their extensive biomedical applications span from drug delivery and bioimaging to therapeutic interventions and regenerative medicine, showcasing the significance of their rational design and fabrication to meet specific requirements and optimize their theranostic performance. Additionally, we offer insights into the future prospects and potential challenges regarding silicon-composed nanomedicine and biomaterials. By shedding light on these exciting research advances, we aspire to foster further progress in the biomedical field and drive the development of innovative silicon-composed nanomedicine and biomaterials with transformative applications in biomedicine.

Effects of nanoplastics exposure on ingestion, life history traits, and dimethyl sulfide production in rotifer Brachionus plicatilis.

Microplastics (MPs) and nanoplastics (NPs) have gained global concern due to their detrimental effects on marine organisms. We investigated the effects of 80 nm polystyrene (PS) NPs on life history traits, ingestion, and dimethyl sulfide (DMS) and dimethylsulfoniopropionate (DMSP) production in the rotifer Brachionus plicatilis. Fluorescently labeled 80 nm PS NPs were ingested by the rotifer B. plicatilis and accumulated in the digestive tract. The lethal rates of B. plicatilis exposed to NPs were dose-dependent. High concentrations of PS NPs exposure had negative effects on developmental duration, leading to prolonged embryonic development and pre-reproductive periods, shortened reproductive period, post-reproductive period, and lifespan in B. plicatilis. High concentrations of PS NPs exposure inhibited life table demographic parameters such as age-specific survivorship and fecundity, generation time, net reproductive rate, and life expectancy. Consequently, the population of B. plicatilis was adversely impacted. Furthermore, exposure to PS NPs resulted in a reduced ingestion rate in B. plicatilis, as well as a decreased in DMS, particulate DMSP (DMSPp) concentration, and DMSP lyase activity (DLA), which exhibited a dose-response relationship. B. plicatilis grazing promoted DLA and therefore increased DMS production. PS NPs exposure caused a decline in the increased DMS induced by rotifer grazing. Our results help to understand the ecotoxicity of NPs on rotifer and their impact on the biogeochemical cycle of dimethylated sulfur compounds.

Palladium-Catalyzed Hydrogenation of Black Barium Titanate for Multienzyme-Piezoelectric Synergetic Tumor Therapy.

Piezocatalytic tumor therapy is an emerging reactive oxygen species (ROS)-generating therapeutic approach that relies on piezoelectric polarization under ultrasound (US) irradiation. Optimizing ROS production is a primary objective for enhancing treatment efficiency. In this study, oxygen-vacancy-rich Pd-integrated black barium titanate (BTO) nanoparticles are rationally engineered to boost the ROS generation efficiency via the introduction of Pd. Pd-catalyzed hydrogenation at low temperatures narrows the bandgap of BTO and reduces the recombination rate of electron-hole pairs. Furthermore, Pd has dual-enzyme-mimicking characteristics, including peroxidase- and catalase-mimicking activities, which further heighten the therapeutic efficacy by enhancing ROS production and reversing the hypoxic tumor microenvironment. Importantly, the dual enzymatic activity of Pd can be amplified by multiple redox processes sparked by the piezoelectric potential under US stimulation, resulting in bilaterally enhanced multienzyme-piezoelectric synergetic therapy. In vitro and in vivo results confirm high tumor inhibition in murine breast cancer cells. This work stresses the critical effects of defect engineering-optimized piezodynamic tumor therapy.

Preparation of rabbit polyclonal antibody and development and identification of quantitative ELISA detection method for pertussis toxin / 中国生物制品学杂志

@#Objective To prepare rabbit polyclonal antibodies against pertussis toxin(PT) and develop a double antibody sandwich ELISA for quantitative determination of PT antigen,identify and apply the method.Methods The rabbit polyclonal antibody against PT was prepared by immunizing Chinchilla rabbit with PT using traditional method.The reaction conditions of ELISA system were optimized,the double antibody sandwich ELISA method for quantitative determi-nation of PT was developed,and the specificity,linearity,accuracy,precision and sensitivity were verified.The developed method was used to detect PT antigen content in fimbriae proteins(FIM) stock solution of samples during detoxification and other purification process of pertussis antigen.Results The working condition of double antibody sandwich ELISA for detection of PT antigen content was the coating concentration of PT rabbit polyclonal antibody of 1 μg/mL,and the enzyme-labeled antibody dilution of 1:8 000.This detection system showed specific reaction with PT purified protein,but had no cross reaction with filamentous hemagglutinin,diphtheria toxoid and tetanus toxoid;the linear detection range of the developed double antibody sandwich ELISA was within 25—400 ng/mL;the recovery rates of PT at high,moderate and low concentrations were 103.27%,91.48% and 103.52%,respectively;both the intra-and inter-coefficients of variation(CVs)were less than 10%;the sensitivity of the method was 20.719 ng/mL,and the detection limit was 41.438 ng/mL.Thirty-five batches of samples were detected under five different detoxification process conditions and at different sampling time points,and the changes of antigen content were all consistent with the trend of detoxification reaction.Conclusion The PT rabbit polyclonal antibody was successfully prepared,and a double antibody sandwich ELISA with high precision and accuracy was developed for the quantitative determination of PT antigen content,which can be used for the antigen content detection of chemically detoxified samples in the production process of component DPT vaccines

Reactive X (where X = O, N, S, C, Cl, Br, and I) species nanomedicine.

Reactive oxygen, nitrogen, sulfur, carbonyl, chlorine, bromine, and iodine species (RXS, where X = O, N, S, C, Cl, Br, and I) have important roles in various normal physiological processes and act as essential regulators of cell metabolism; their inherent biological activities govern cell signaling, immune balance, and tissue homeostasis. However, an imbalance between RXS production and consumption will induce the occurrence and development of various diseases. Due to the considerable progress of nanomedicine, a variety of nanosystems that can regulate RXS has been rationally designed and engineered for restoring RXS balance to halt the pathological processes of different diseases. The invention of radical-regulating nanomaterials creates the possibility of intriguing projects for disease treatment and promotes advances in nanomedicine. In this comprehensive review, we summarize, discuss, and highlight very-recent advances in RXS-based nanomedicine for versatile disease treatments. This review particularly focuses on the types and pathological effects of these reactive species and explores the biological effects of RXS-based nanomaterials, accompanied by a discussion and the outlook of the challenges faced and future clinical translations of RXS nanomedicines.

Identification of two novel papillomaviruses in belugas.

Introduction: Papillomaviruses (PVs) can cause hyperplasia in the skin and mucous membranes of humans, mammals, and non-mammalian animals, and are a significant risk factor for cervical and genital cancers. Methods: Using next-generation sequencing (NGS), we identified two novel strains of papillomavirus, PV-HMU-1 and PV-HMU-2, in swabs taken from belugas (Delphinapterus leucas) at Polar Ocean Parks in Qingdao and Dalian. Results: We amplified the complete genomes of both strains and screened ten belugas and one false killer whale (Pseudorca crassidens) for the late gene (L1) to determine the infection rate. In Qingdao, 50% of the two sampled belugas were infected with PV-HMU-1, while the false killer whale was negative. In Dalian, 71% of the eight sampled belugas were infected with PV-HMU-2. In their L1 genes, PV-HMU-1 and PV-HMU-2 showed 64.99 and 68.12% amino acid identity, respectively, with other members of Papillomaviridae. Phylogenetic analysis of combinatorial amino acid sequences revealed that PV-HMU-1 and PV-HMU-2 clustered with other known dolphin PVs but formed distinct branches. PVs carried by belugas were proposed as novel species under Firstpapillomavirinae. Conclusion: The discovery of these two novel PVs enhances our understanding of the genetic diversity of papillomaviruses and their impact on the beluga population.

Humanized disulfide-stabilized diabody against fibroblast growth factor-2 inhibits PD-L1 expression and epithelial-mesenchymal transition in hepatoma cells through STAT3.

Fibroblast growth factor 2 (FGF2) plays an important role in tumor angiogenesis. Humanized disulfide-stable double-chain antibody against fibroblast growth factor-2 (anti-FGF2 ds-Diabody) is a small molecule antibody with good tissue permeability and low immunogenicity, which has potential in tumor-targeted therapy. This study intended to investigate the effect of anti-FGF2 ds-Diabody on the migration and expression of programmed death-ligand1 (PD-L1) in hepatocellular carcinoma (HCC) cells. The anti-FGF2 ds-Diabody was expressed under methanol induction and purified with Ni2+ -affinity chromatography. Anti-FGF2 ds-Diabody significantly inhibited cell viability and proliferation in SK-Hep1 and HepG2 cells as confirmed by CCK-8 assays and colony formation assays. Western blot assays indicated that the proliferation of SK-Hep1 and HepG2 cells was inhibited by anti-FGF2 ds-Diabody through inhibiting the phosphorylation activation of AKT and MAPK. The results of transwell and western blot assays showed that the migration and invasion of SK-Hep1 and HepG2 cells were suppressed by anti-FGF2 ds-Diabody by affecting the epithelial-mesenchymal transition (EMT) process. Meanwhile, anti-FGF2 ds-Diabody inhibited the expression of PD-L1, and STAT3 participated in this process. Analysis of RT-PCR and Western blot suggested that fibroblast growth factor receptor 4 inhibitor 1 (FGFR4-IN-1) suppressed the expression of PD-L1, while STAT3 overexpression reversed this inhibitory effect. In addition, overexpression of STAT3 promoted migration and invasion and restored the suppressive effect of anti-FGF2 ds-Diabody on EMT. In conclusion, anti-FGF2 ds-Diabody could inhibit the expression of PD-L1 and EMT of hepatoma cells through FGF2/FGFR4/STAT3 axis. These results suggested that anti-FGF2 ds-Diabody has potential clinical application in inhibiting metastasis and immune escape of hepatocellular carcinoma.

Engineering 2D Multienzyme-Mimicking Pyroptosis Inducers for Ultrasound-Augmented Catalytic Tumor Nanotherapy.

Overcoming apoptosis resistance is necessary to ensure an effective cancer treatment; however, it is currently very difficult to achieve. A desirable alternative for cancer treatment is the targeted activation of pyroptosis, a unique type of programmed cell death. However, the pyroptosis inducers that are efficient for cancer therapy are limited. This work reports the engineering of 2D NiCoOx nanosheets as inducers of the production of harmful reactive oxygen species (ROS), which promote intense cell pyroptosis, and that can be applied to ultrasound (US)-augmented catalytic tumor nanotherapy. The main therapeutic task is carried out by the 2D NiCoOx nanosheets, which have four multienzyme-mimicking activities: peroxidase- (POD), oxidase- (OXD), glutathione peroxidase- (GPx), and catalase- (CAT) mimicking activities. These activities induce the reversal of the hypoxic microenvironment, endogenous glutathione depletion, and a continuous ROS output. The ROS-induced pyroptosis process is carried out via the ROS-NLRP3-GSDMD pathway, and the exogenous US activation boosts the multienzyme-mimicking activities and favors the incremental ROS generation, thus inducing mitochondrial dysfunction. The anti-cancer experimental results support the dominance of NiCoOx nanosheet-induced pyroptosis. This work expands on the biomedical applications of engineering 2D materials for US-augmented catalytic breast cancer nanotherapy and deepens the understanding of the multienzyme activities of nanomaterials.

Nanomedicine-Enabled Sonomechanical, Sonopiezoelectric, Sonodynamic, and Sonothermal Therapy.

Nanomedicine-enabled/augmented ultrasound (US) medicine is a unique area of interdisciplinary research that focuses on designing and engineering functional nanosystems to address the challenging issues in US-based biomedicine, overcoming the shortcomings of traditional microbubbles and optimizing the design of contrast and sonosensitive agents. The single-faceted summary of available US-related therapies is still a significant drawback. Here, The proposal of a comprehensive review on the recent advances of sonosensitive nanomaterials in advancing four US-related biological applications and disease theranostics is aimed. In addition to the mostly explored nanomedicine-enabled/augmented sonodynamic therapy (SDT), the summary and discussion of other sono-therapies and progresses/achievements are relatively lacking, including sonomechanical therapy (SMT), sonopiezoelectric therapy (SPT), and sonothermal therapy (STT). The design concepts of the specific sono-therapies based on nanomedicines are initially introduced. Furthermore, the representative paradigms for nanomedicine-enabled/enhanced US therapies are elaborated according to therapeutic principles and diversity. This review provides an updated and comprehensive review of the field of nanoultrasonic biomedicine, and comprehensively discusses the progress of versatile ultrasonic disease treatments. Finally, the deep discussion on the facing challenges and prospects is expected to promote the emergence and establishment of a new branch of US biomedicine through the rational combination of nanomedicine and US clinical biomedicine.

Topology regulation of nanomedicine for autophagy-augmented ferroptosis and cancer immunotherapy.

Iron accumulation and lipid peroxidation form the basis of ferroptosis, potentially circumventing the limitations of apoptosis in cancer treatment. Owing to the lack of potent ferroptosis inducers, the development of efficient ferroptosis-based therapeutic agents and protocols against cancers is highly challenging. Inspired by the topological effect of nanoparticles in modulating cellular function/status, a specific tetrapod ferroptosis-inducer iron-palladium (FePd) nanocrystal was rationally engineered for physically activated autophagy-augmented ferroptosis and enhanced cancer immunotherapy. Specifically, the tetrapod FePd nanocrystal featured strong peroxidase-/glutathione oxidase-mimicking bioactivities, which promoted cancer cell ferroptosis. The special spiky morphology and nanostructure of the FePd nanocrystal simultaneously induced autophagy, which augmented ferroptosis in cancer cells and triggered the release of inflammatory cytokines in macrophages for strengthening anti-PD-L1-antibody mediated immunotherapy, synergistically achieving the maximal antineoplastic effect in three tumor-bearing animal models. This unique physical activation strategy for efficient cancer treatment via precise morphological tuning represents a paradigm for nanomedicine design for efficient tumor treatment.

Manganese-enriched photonic/catalytic nanomedicine augments synergistic anti-TNBC photothermal/nanocatalytic/immuno-therapy via activating cGAS-STING pathway.

As the clinical efficacy of immunotherapy for triple-negative breast cancer (TNBC) remains limited, exploring new immunotherapy approaches is still indispensable. Mn2+ has been proven as a cGAS-STING agonist to remarkably enhance antitumor immunity. Here, we report a combined tumor-therapeutic strategy based on Prussian blue (PB)-mediated photothermal therapy with Mn2+-augmented immunotherapy by synergistically activating the cGAS-STING pathway. Mn-enriched photonic nanomedicine (MnPB-MnOx) were constructed by integrating MnOx onto the surface of Mn-doped PB nanoparticles. All components of MnPB-MnOx are biocompatible and biodegradable, wherein sufficient Mn are endowed through rational nanostructure design, conferring easier cGAS-STING activation. Additionally, tumor hyperthermia strengthened by MnPB under near-infrared light radiation, synergistic with the generation of reactive oxygen species catalyzed by MnOx, double hits cancer cells to release abundant tumor-associated antigens for further promoting immune response stimulation. The local anti-TNBC efficacy of photothermal/immuno-therapy has been proven effective in subcutaneous 4T1-bearing mice. Especially, it has been systematically demonstrated in bilateral orthotopic 4T1-bearing mice that the as-proposed treatment could successfully activate innate and adaptive immunity, and local therapy could engender systemic responses to suppress the distant tumors. Collectively, this work represents a proof-of-concept for a non-invasive Mn-based tumor-immunotherapeutic modality, providing a paradigm for the immunotherapy of metastatic-prone tumors.

Engineering Fe/Mn-doped zinc oxide nanosonosensitizers for ultrasound-activated and multiple ferroptosis-augmented nanodynamic tumor suppression.

As an effective tumor-therapeutic modality, ultrasound-triggered sonodynamic therapy (SDT) has been extensively explored to induce cancer cell death by activating sonosensitizers to generate reactive oxygen species (ROS). However, the traditional inorganic semiconductor-based sonosensitizers still suffer from inefficient ROS production because of the low separation efficiency of electrons and holes (e-/h+) and their fast recombination. Herein, the iron (Fe) and manganese (Mn) co-doped zinc oxide nanosonosensitizers have been rationally designed and engineered for augmenting the SDT efficiency against tumor by inducing both multiple ferroptosis and apoptosis of tumor cells. The Fe/Mn component was co-doped into the nannostructure of ZnO nanosonosensitizers, which not only catalyzed the Fenton reaction in the hydrogen peroxide-overexpressed tumor microenvironment to produce ROS, but also depleted intracellular glutathione to suppress the consumption of ROS. The doping nanostructure in the engineered nanosonosensitizers substantially augmented the SDT efficacy of ZnO nanosonosensitizers by promoting the separation and hindering the recombination of e-/h+ under ultrasound activation. The multiple ferroptosis and apoptosis in the enhanced SDT effect of Fe/Mn co-doped ZnO nanosonosensitizers were solidly demonstrated both in vitro and in vivo on tumor-bearing mice in accompany with the detailed mechanism assessment by RNA sequenching. This work provides a distinct strategy to augment the nanomedicine-enabled SDT efficency by engineering the inorganic semiconductor-based nanosonosensitizers with transitional metal doping and inducing multiple cell-death pathways including ferroptosis.

A Calcium Fluoride Nanozyme for Ultrasound-Amplified and Ca2+ -Overload-Enhanced Catalytic Tumor Nanotherapy.

The anticancer mechanism of nanozymes is dominantly associated with the capacity for generation of reactive oxygen species (ROS) caused by the valence change of metal elements. However, very little research is focused on and has achieved the exploration and development of enzyme-mimicking activities of valence-invariable metal compounds. Herein, a distinct valence-invariable calcium fluoride (CaF2 ) nanozyme with ultrasound (US)-enhanced peroxidase (POD)-mimicking activity is rationally designed and engineered for efficient calcium (Ca2+ )-overload-enhanced catalytic tumor nanotherapy, which is the first paradigm of Ca-based nanozymes for catalytic cancer treatment. The release of exogenous Ca2+ ions from CaF2 nanocrystals and deleterious ROS generation derived from US-amplified POD-mimicking properties facilitate intracellular Ca2+ accumulation and achieve Ca2+ -overload-induced mitochondrial dysfunction through introducing exogenous Ca2+ ions and regulating calcium-pumping channels of neoplastic cells. Especially, US as an exogenous energy input is capable of substantially amplifying POD-mimicking catalytic activities of CaF2 nanozyme, ultimately achieving efficient anti-neoplastic outcome on both 4T1 breast tumor and H22 hepatic carcinoma animal models. Such a discovery of enzyme-like activity of valence-invariable metal compounds can broaden the cognition scope of nanozymes and effectively serves the field of catalytic and chemoreactive nanomedicine.

Microorganism-enabled photosynthetic oxygeneration and ferroptosis induction reshape tumor microenvironment for augmented nanodynamic therapy.

Nanodynamic therapy (NDT) based on reactive oxygen species (ROS) generation has been envisioned as a distinct modality for efficient cancer treatment. However, insufficient ROS generation and partial ROS consumption frequently limit the theraputic effect and outcome of NDT owing to the low oxygen (O2) tension and high glutathione (GSH) level in tumor microenvironment (TME). To circumvent these critical issues, we herein proposed and engineered the biodegradable GSH-depletion Mn(III)-riched manganese oxide nanospikes (MnOx NSs) with the photosynthetic bacterial cyanobacteria (Cyan) as a high-efficient and synergistic platform to reshape TME by simultaneously increasing oxygen content and decreasing GSH level. Specifically, under the trigger of acidity, MnOx NSs reacted with photosynthetic oxygen can generate toxic singlet oxygen (1O2). Moreover, MnOx NSs significantly reduced intracellular GSH, resulting in decreased GPX4 activity, which induced tumor cell non-apoptotic ferroptosis. Consequently, this combined strategy based on coadministration with Cyan and MnOx NSs demonstrated the superior antitumor efficacy via amplification of oxidative stress in 4T1 tumor-bearing mice for the synergetic oxygen-augmented nanodynamic/ferroptosis therapy. This work highlights a facile synergistic micro-/nano-system with the specific capability of reshaping TME to augment the sensitivity and therapeutic efficacy of NDT in solid hypoxic tumor therapy.

Constructing a heparin-modified penile decellularized scaffold to improve re-endothelialization in organizational reconstruction.

Background: Due to the unique anatomy and complex function of the penis, the reconstruction of penile defect is fraught with great challenges. The current standard methods are limited by numerous complications and insufficient donor sites. While functional vascularized penile tissue engineering offers a novel way to address this problem, revascularization remains the primary concern. Methods: In this study, a penile scaffold with associated modifications was constructed. The performance of decellularized penile scaffolds (DPSs) was improved by conjugation with heparin (HEP) and reseeding with human umbilical vein endothelial cells (HUVECs). There were three groups according to the modifications, including native DPSs, HEP-DPSs, HEP-HUVECs-DPSs. After perfusing with 1% Triton X-100/0.1% ammonium hydroxide solution, the cellular components were removed. Subsequently, the covalent binding of heparin in the DPSs was performed with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide, followed by reseeding with HUVECs. Scaffolds were implanted into the backs of rats and the implanted tissues were harvested at 1, 2, 3, and 4 weeks. Then hematoxylin and eosin (H&E) staining and immunofluorescence assays were performed to assess the degree of angiogenesis. Results: The native DPSs retained the extracellular matrix and heparinized modification. The H&E results indicated that more HUVECs covered the inner surface of tubular structures in the HEP-DPSs group compared to the native DPSs group. The number of vessels in the HEP-HUVECs-DPSs was significantly increased compared to the control scaffolds at all time points. Conclusions: These results suggested that, compared to the native DPS, heparin-conjugated scaffolds provided a superior environment for the growth of HUVECs and the modified methods provided a perspective for overcoming the obstacles in tissue engineering of transplantable penile tissues and the establishment of a functional vasculature.

Transcutaneous tumor vaccination combined with anti-programmed death-1 monoclonal antibody treatment produces a synergistic antitumor effect.

Transcutaneous immunization (TCI) has the advantages of safety, high efficiency, non-invasiveness and convenient use. The key for a TCI system is transdermal targeted delivery of antigen to dendritic cells (DCs), the most powerful antigen presenting cells. DCs also play an important role in tumor immunotherapy, which provides a huge imagination for the application of TCI to tumor treatment. In this study, a transcutaneous tumor vaccine (TTV) delivery system was developed using the electrospun silk fibroin (SF) and polyvinyl alcohol (PVA) composite nanofibrous patch loaded with mannosylated polyethyleneimine (PEIman)-modified ethosome (Eth) (termed Eth-PEIman). Eth-PEIman showed a good performance in targeting DCs, and the carriers loaded with antigen (encapsulated in Eths) and adjuvant (absorbed in PEIman) were observed effectively induce DCs maturation in vitro. With the tyrosinase-related protein-2 (TRP2) peptide as antigen and oligodeoxynucleotides containing unmethylated CpG motifs as adjuvant, the TTV-loaded patches (TTVP) significantly inhibited the growth of melanoma in a syngeneic mouse model for melanoma by subcutaneous injection of B16F10 cell lines. Moreover, the combined application of the TTVP and anti-programmed death-1 monoclonal antibody (aPD-1) produced a synergistic antitumor effect, which could be related to the infiltration of more CD4+ and CD8+ T cells in the tumor tissues. The application of TTVP also increased the expression of IL-12, which may be part of the mechanism of synergistic antitumor effect between the TTVP and aPD-1. These results suggest that the combination of the TTVP and immune checkpoint blockers could be an effective strategy for tumor treatment. STATEMENT OF SIGNIFICANCE: Transcutaneous immunization has the advantages of safety, high efficiency, non-invasiveness and convenient use. In this study, a novel transcutaneous tumor vaccine patch (TTVP) was developed using tumor antigens-loaded ethosomes that can target dendritic cells percutaneously. Our data demonstrated that the TTVP can significantly inhibit tumor growth. Furthermore, the combination of TTVP and aPD-1 produced a synergistic anti-melanoma effect. Considering its convenience and non-invasiveness, this TTVP system could find good application prospects in immunotherapy. The combination of TTVP and aPD-1 could be a useful strategy for the prevention and treatment of tumors.