BREAST CANCER RESEARCH
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2025
·Vol. 27
·期 1
·1-19
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IF 5.6
Kong Linghui,Hu Song,Zhao Ying,Huang Yan,Xiang Xiaobing,Yu Yang,Mao Xiaochun,Xie Kangjie,Zhu Xiaoyan,Xu Pingbo
Background The mechanisms underpinning neoadjuvant chemotherapy-induced vascular endothelial injury in breast cancer remain elusive. Our study aims to demonstrate that Neutrophil Extracellular Traps (NETs) play a pivotal role in neoadjuvant chemotherapy-induced vascular endothelial injury in breast cancer, elucidating that chemotherapy-induced upregulation of Solute Carrier 11a1 (Slc11a1) modulates Reactive Oxygen Species (ROS) generation, which may be critical for NETs formation.Methods We investigated the impact of neoadjuvant chemotherapy for breast cancer on NETs formation and vascular endothelial injury by analyzing NETs dsDNA and serum markers in patients, cells, and chemotherapy mouse models. RNA sequencing of neutrophils from chemotherapy mouse models was performed to identify the potential NETs formation-associated gene Slc11a1, which was further validated through cellular and animal experiments by assessing Slc11a1 expression, intracellular ferrous ion content, and ROS levels. Knockdown of Slc11a1 in human neutrophils and mouse models were also performed to further confirm the phenotypic results.Results Our study revealed that plasma NETs formation and endothelial injury markers were significantly elevated in breast cancer patients undergoing docetaxel & carboplatin (TCb) neoadjuvant chemotherapy, compared to controls. In these patients, NETs formation was associated with the augmentation of endothelial injury markers. Chemotherapy mouse models demonstrated that TCb treatment markedly elevated NETs formation and endothelial injury, which can be mitigated by CI-amidine, a protein-arginine deiminase inhibitor. In human neutrophils, we demonstrated that the TCb chemotherapeutic agents (combination of docetaxel and carboplatin) induced the formation of NETs, which subsequently facilitated damage to human umbilical vein endothelial cells in vitro. RNA sequencing of mouse neutrophils identified Slc11a1 as a key NETs formation-related gene, which was upregulated by TCb chemotherapy in neutrophils, leading to increased intracellular ferrous ion content and ROS generation. Knockdown of Slc11a1 in human neutrophils and mouse models demonstrated its reversal effect on TCb-induced ferrous ion upregulation, ROS generation, and NETs formation.Conclusion sOur research underscores the capacity of TCb neoadjuvant chemotherapy in breast cancer to augment NETs formation in neutrophils through Slc11a1-mediated ROS generation, which is linked to vascular endothelial injury. Our study elucidates the potential mechanisms underlying perioperative vascular endothelial injury in breast cancer patients undergoing neoadjuvant chemotherapy, offering novel insights into perioperative therapeutic management strategies for these patients.
研究领域:
肿瘤学
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免疫学
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分子生物学
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PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Zhipeng Li,Yaoyao Wu,Jialin Wu,Cheng Zhang,Xinsheng Cheng,Hongzhen Zhang,Shikai Wang
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized clinically by recurrent abdominal pain and bloody diarrhea, for which there is currently a lack of curative therapeutic strategies. In recent years, neutrophil extracellular traps (NETs) have been identified as playing a key role in the pathogenesis of UC, emerging as a potential therapeutic target. Although deoxyribonuclease I (DNase I) can exert therapeutic effects by degrading the DNA backbone of NETs, its clinical application is limited by inherent drawbacks, including poor in vivo stability, low bioavailability, and inefficient penetration of biological barriers. Herein, this study constructed a biomimetic membrane-based nanodelivery system. Initially, zeolitic imidazolate framework-8 (ZIF-8) was used to encapsulate DNase I, forming ZD nanoparticles to enhance enzymatic stability. Subsequently, these nanoparticles were coated with bacterial outer membrane vesicles (BOMVs), yielding the final BVZD composite system, designed to improve targeting to inflammatory sites. The BVZD system exhibited suitable particle size, good biocompatibility, and a demonstrated ability to specifically accumulate in the inflamed intestinal regions of a UC model. Both in vitro and in vivo experiments confirmed that BVZD effectively degraded NETs, suppressed endoplasmic reticulum stress (ERS) by downregulating the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), and promoted the repair of the intestinal epithelial barrier. These findings highlight the promising therapeutic potential of BVZD for the treatment of UC.
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CHEMICAL ENGINEERING JOURNAL
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2026
·
IF 12.5
Liya Yang,Na Yin,Tongge Wang,Ruilin Chao,Qiang Yang,Yifei Gao,Shenyao Jin,Yiman Chen,Jian Li,Ling Guo,Min Feng
Sepsis is a life-threatening syndrome caused by dysregulated host responses to bacterial infection. Persistence of intracellular bacteria within macrophages sustains excessive reactive oxygen species (ROS) production, disrupts redox homeostasis and amplifies inflammatory cascades that accelerate disease progression. Here, we developed an in situ arming strategy that generated potent antibacterial effectors by programming neutrophil extracellular traps with redox-modulating liposomes (SUPER-NETs) for targeted sepsis treatment. SUPER-NETs are formed in vivo through neutrophil hijacking and co-migration to infection sites, and subsequent functionalization of expelled NETs. Notably, SUPER-NETs established a neutrophil–macrophage bridging interaction that enabled precise and efficient elimination of intracellular bacteria. In parallel, SUPER-NETs alleviated macrophage oxidative stress and dampened cytokine storm by activating the Nrf2 signaling pathway. In a severe murine sepsis model, systemic administration of SUPER-NETs conferred superior antibacterial efficacy, attenuated multi-organ injury, and significantly improved survival. Therefore, this in situ arming strategy of SUPER-NETs offers a promising therapeutic paradigm for sepsis by precisely eliminating intracellular bacteria and orchestrating macrophage redox homeostasis, with potential implications for the treatment of sepsis and other severe infectious diseases.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Huan Zeng,Jingyi Qi,Qiyi Chen,Ruowei Zhang,Chen Guo,Jinghua Zhao,Huimei Liang,Junlong Sun,Wei Wang,Houhui Song
Nanoplastics (NPs), highly prevalent due to large-scale plastic production, and glyphosate (Gly), the most utilized herbicides worldwide, are ubiquitous environmental contaminants. Growing concerns highlight that NPs can act as vectors for various pollutants like Gly, but their combined toxic effects in mammals and the underlying mechanisms remain poorly understood. In this study, the hepatotoxicity and potential mechanisms under the exposure of polystyrene nanoplastics (PSNPs) and/or Gly in vivo and in vitro were investigated. Mice were treated with PSNPs (25 mg/kg/day) and/or Gly (50 mg/kg/day) by oral gavage for 5 weeks. Results showed that exposure to PSNPs or Gly caused liver injury in mice, with co-exposure resulting exacerbated hepatotoxicity, evidenced by increased neutrophil infiltration and ultrastructural damages, elevated oxidative stress (LPO, H 2 O 2 , T-AOC and CAT), increased neutrophil chemokines (CCL2, CXCL12) and marker of neutrophil extracellular traps (NETs) formation (MPO), and upregulated pyroptosis-related factors (TLR4, NF-κB, NLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-18). In addition, a co-culture system of peripheral blood neutrophils (PBNs) and AML12 cells was established, revealing that co-exposure amplified ROS production, NETs formation (SYTOX Green staining) and pyroptosis. Notably, inhibition of the NLRP3 inflammasome significantly reduced NETs production, and degradation of NETs substantially decreased pyroptosis, demonstrating feedback between NETs and the NLRP3 inflammasome that drives inflammation induced by PSNPs and Gly. These results highlight that co-exposure exacerbated NETs-mediated pyroptosis through NLRP3 inflammasome activation. Our study equips new reference for understanding the mechanistic insights and health implications of the combined toxicity of PSNPs and Gly.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Chang Liu,Sen Tan,Weili Xue,Wenkang Tu,Hengrui Liu,Meng Yuan,Yuchu He,Xuwu Zhang,Dawei Gao
Mechanistic Insight: Identified a NETs-mediated arginine depletion pathway that suppresses T cell infiltration and effector function in the tumor microenvironment (TME). • Biomimetic Design: Developed a neutrophil membrane-camouflaged piezoelectric nanodrug (gZn-PCN@NEM) for targeted delivery to tumor sites. • Targeted NETs Degradation: Piezoelectric catalysis enables efficient degradation and functional inactivation of NETs within the TME. • Barrier Breakdown: Elimination of NETs dismantles the physical barrier, significantly enhancing T cell infiltration into tumors. • Metabolic Restoration: NETs disruption restores local arginine levels in the TME, providing essential metabolic support for T cell proliferation and activation. • Enhanced Immunotherapy: Synergistic regulation of the physical barrier and arginine metabolism markedly enhances T cell-mediated antitumor immune responses. • Therapeutic Strategy: This work proposes a dual-function immunomodulatory strategy integrating NETs disruption with arginine rescue to overcome tumor immunosuppression. Arginine depletion in the tumor microenvironment (TME) directly deprives T cells of key metabolic substrates required for proliferation and differentiation, thereby inhibiting their antitumor effects. This process is closely associated with neutrophil extracellular traps (NETs). Under inflammatory stimulation, neutrophils generate hypochlorous acid (HClO) by intracellular enzymes and release chromatin and proteases to form NETs. Notably, arginase-1 (ARG1) within NETs accelerates arginine degradation, impairing the metabolic supply of T cells and forming the immunosuppressive TME. Herein, we construct a piezoelectric catalytic nanodrug gZn-PCN@NEM to degrade NETs by doping polymerized carbon nitride (PCN) nanosheets with gradient Zn 2+ and coating them with neutrophil membranes (NEM). This biomimetic camouflage enables neutrophils to rapidly internalize gZn-PCN@NEM and transport it to the tumor site. Under ultrasonic (US) stimulation, gZn-PCN@NEM decomposes HClO in NETs to produce chlorine radicals (Cl·), which induce DNA double-strand breaks of tumor cells, thereby efficiently killing them. The decomposition of HClO triggers the structural collapse of NETs and functional inactivation of ARG1, thereby restoring arginine levels in the TME and promoting T cell proliferation and activation. This work proposes a piezoelectric-catalytic “nets-breaking and source-rescuing” strategy to rescue arginine by degrading NETs, providing a promising approach for enhancing cancer immunotherapy.
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SENSORS AND ACTUATORS B-CHEMICAL
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2012
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IF 3.898
Xianfeng Wang,Yang Si,Jialin Wang,Bin Ding,Jianyong Yu,Salem S. Al-Deyab
A novel strategy for highly sensitive colorimetric detection of gaseous formaldehyde was developed based on Methyl Yellow-impregnated electro-spinning/netting (ESN) nylon 6 nano-fiber/nets (NFN). The sensor presented a significant reflectance intensity decreasing band at 550 nm which induce the visual color changes from yellow to red after exposure to formaldehyde and allowed for the detection of formaldehyde with a low detection limit of 50 ppb. Upon exposure to a series of volatile organic compounds (VOCs), only formaldehyde could induce a yellow-to-red color change observable by the naked eye, which clearly exhibited that Methyl Yellow-impregnated nylon 6 NFN membranes could act as highly selective and sensitive strips to detect formaldehyde with minor interference from other VOCs. Additionally, the colorimetric sensor showed good reproducibility under cyclic sensing experiments. Furthermore, the colorimetric responses were visualized quantitative by using a color-differentiation map prepared form converted RGB (red, green and blue) values. As-prepared Methyl Yellow-impregnated nylon 6 NFN sensor strips successfully combined with the visualized detection of color map and fascinating structure of NFN membranes, which indicated promising composite materials as a simple and economical alternative to replace the traditional formaldehyde sensors and facilitated the design and development of other label-free colorimetric sensors toward various analytes based on the NFN template.
研究领域:
材料科学
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环境科学
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化学传感
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PHYTOTHERAPY RESEARCH
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2025
·
IF 6.3
Lin Cheng,Zhirui Du,Xueqiao Yan,Manju Che,Guoguo Zhi,Xiuying Ma,Funeng Geng,Baojie Li
Atopic dermatitis (AD) is a chronic inflammatory skin disorder with limited effective treatment. Sophora flavescens Aiton (Kushen) exhibits anti-inflammatory properties, but its key active components and mechanisms against AD remain unclear. This study aimed to identify its therapeutic compounds and the underlying molecular mechanisms. Network pharmacology and ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry were applied to screen for the potential bioactive compounds from Kushen, which were validated in AD mouse models. Formononetin (FMN) was topically administered to evaluate its curative efficacy through histopathological and immunofluorescent staining of skin lesions. Transcriptomic profiling explored the molecular mechanisms, with subsequent validation of neutrophil extracellular traps (NETs)-associated markers by immunofluorescent staining and western blotting. Co-treatment with PAD4 inhibitor GSK484 and molecular docking were used to study the underlying mechanisms. The study identified FMN as an important active component in Kushen, which showed therapeutic effects comparable to dexamethasone in AD models. FMN normalized cutaneous hyperplasia, reduced infiltration of CD3 + T cells, mast cells, and neutrophils, and suppressed inflammatory cytokine expression. Mechanistically, FMN inhibited NETs formation evidenced by decreased levels of citrullinated histone H3 (citH3), myeloperoxidase (MPO), and peptidylarginine deiminase 4 (PAD4). GSK484 co-treatment showed non-synergistic effects, suggesting that FMN suppresses NETs formation primarily through PAD4/MPO inhibition, which was confirmed by molecular docking. These findings highlight FMN as a primary anti-AD constituent of Kushen, therapeutically suppressing NETs-driven crosstalk of innate and adaptive immunity. FMN's multitarget mechanisms provide mechanistic insights and position it as a candidate for AD treatment.
研究领域:
药理学
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免疫学
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皮肤科学
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生物信息学
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分子生物学
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PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2021
·Vol. 31
·期 42
·2105089
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IF 18.808
Lianghan Zhu,Zhaoting Li,Ning Liu,Honghao Sun,Yixin Wang,Minjie Sun
Neutrophil extracellular traps (NETs), consisting of chromatin DNA filaments coated with granule proteins, promote metastasis by enhancing tumor cell migration to distant organs. Recent studies indicate that NETs adhere to cancer cell membranes and enhance cell motility significantly to induce liver metastasis in patients with breast and colon cancers. Herein, a dynamically deformable protein delivery strategy is developed to prevent liver metastasis by disassembling NETs. Specifically, poly amino acid conjugating with polyethylene glycol (PAAP) is explored and synthesized for DNase-1 delivery. Notably, PAAP/DNase-1 degrades chromatin to induce apoptosis, followed by cell membrane rupture and remaining DNase-1 releases to the extracellular. More importantly, the released DNase-1 disassembles NET-DNA to prevent liver metastasis induced by NET. In all, PAAP/DNase-1 treatment not only suppresses tumor growth by degrading intracellular chromatin, but also prevents the liver metastasis by disassembling the NET-NDA. This strategy may provide brand-new inspiration to prevent the liver metastasis fundamentally in patients with metastatic colon and breast cancer.
研究领域:
癌症生物学
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药学
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分子生物学
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免疫学
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高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2022
·Vol. 180
·期 3
·287-307
·
IF 9.473
Li Li,Xulin Xu,Keyu Lv,Guijuan Zheng,Hao Wang,Shuai Chen,Lang Huang,Yi Liu,Yadong Zhang,Zhaoming Tang,Lili Zhang,Jinyu Wang,Jianlin Qiao,Hongliang Li,Xuanbin Wang,Guangmin Yao,Chao Fang
Background and Purpose Thrombosis is a major cause of morbidity and mortality worldwide. Platelet activation by exposed collagen through glycoprotein VI (GPVI) and formation of neutrophil extracellular traps (NETs) are critical pathogenic factors for arterial and venous thrombosis. Both events are regulated by spleen tyrosine kinase (Syk)-mediated signalling events. Asebogenin is a dihydrochalcone whose pharmacological effects remain largely unknown. This study aims to investigate the antithrombotic effects of asebogenin and the underlying molecular mechanisms. Experimental Approach Platelet aggregation was assessed using an aggregometer. Platelet P-selectin exposure, integrin activation and calcium mobilization were determined by flow cytometry. NETs formation was assessed by SYTOX Green staining and immunohistochemistry. Quantitative phosphoproteomics, microscale thermophoresis, in vitro kinase assay and molecular docking combined with dynamics simulation were performed to characterize the targets of asebogenin. The in vivo effects of asebogenin on arterial thrombosis were investigated using FeCl 3 -induced and laser-induced injury models, whereas those of venous thrombosis were induced by stenosis of the inferior vena cava. Key Results Asebogenin inhibited a series of GPVI-induced platelet responses and suppressed NETs formation induced by proinflammatory stimuli. Mechanistically, asebogenin directly interfered with the phosphorylation of Syk at Tyr525/526, which is important for its activation. Further, asebogenin suppressed arterial thrombosis demonstrated by decreased platelet accumulation and fibrin generation and attenuated venous thrombosis determined by reduced neutrophil accumulation and NETs formation, without increasing bleeding risk. Conclusion and Implications Asebogenin exhibits potent antithrombotic effects by targeting Syk and is a potential lead compound for the development of efficient and safe antithrombotic agents. Graphical
研究领域:
药理学
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血液学
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分子生物学
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PubMed
高影响因子
BIOMATERIALS
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2025
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IF 12.9
Yuchao Sun,Jian He,Weiyu Chen,Yongfang Wang,Kai Wang,Min Zhou,Yichun Zheng
High-dose radiation therapy is a widely used clinical strategy to inhibit tumor growth. However, the rapid generation of excessive reactive oxygen species (ROS) triggers the formation of neutrophil extracellular traps (NETs), which capture free tumor cells in the bloodstream, promoting metastasis. In this study, we developed a hybrid nanoparticle composed of DNase I and gold (DNase I@Au) to enhance radiotherapy efficacy while mitigating metastasis by precisely eliminating NETs. The DNase I@Au nanoparticles, administered via aerosol inhalation, are efficiently delivered to lung tumor tissue, improving radiosensitization and reducing tumor size. Crucially, the nanoparticles could gradually release DNase I, effectively degrading ROS-induced NETs and preventing the interaction of free malignant cells with tumor sites or vasculature, thereby inhibiting metastasis. Therefore, we provide an enzyme and sensitizer co-loaded strategy that offers a promising approach to improve the therapeutic outcome of radiotherapy and reduce the risk of lung cancer metastasis under ROS stimulation.
研究领域:
肿瘤学
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纳米技术
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放射生物学
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药学
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PubMed
高影响因子
Nanoscale
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2025
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IF 5.1
Yuan Quan,Yan Yuan,Kejin Chen,Ting Li,Jing Li,Mengxing Zhang,Rongying Shi,Shanshan He,Lin Li,Xun Sun,Tao Gong,Ling Zhang,Zhirong Zhang,Qing Lin
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high recurrence rates, limited therapeutic options, and a strong propensity for spontaneous lung metastasis. Increasing evidence indicates that neutrophil extracellular traps (NETs) significantly promote TNBC progression, immune evasion, and metastatic dissemination, highlighting NETs inhibition as a promising therapeutic strategy. Herein, we developed a dual pH/ROS-responsive nanoplatform (pH/ROS@(PTX/SIV)) constructed from acetylated dextran (Ace-DEX) and phenylboronic acid-modified dextran (PBAP-DEX), and further functionalized with the fibronectin-targeting peptide CREKA to achieve tumor-specific accumulation. The nanoplatform enables controlled, microenvironment-responsive release of paclitaxel (PTX) and the neutrophil elastase inhibitor sivelestat (SIV) in acidic and oxidative tumor tissues. The optimized nanoparticles exhibited uniform size, high encapsulation efficiencies, and robust dual-responsive drug release. In vitro, CREKA modification markedly enhanced cellular uptake and tumor-targeting efficiency, while the dualloaded system showed superior cytotoxicity against TNBC cells. In orthotopic TNBC mouse models, pH/ROS@(PTX/SIV) significantly suppressed primary tumor growth, prolonged survival, and critically inhibited spontaneous lung metastasis.Mechanistically, the formulation effectively blocked NETs formation both in isolated primary neutrophils and in tumor tissues, thereby disrupting NETs-mediated prometastatic signaling. Furthermore, the nanoplatform displayed favorable systemic safety with negligible organ toxicity. This dual-responsive, NET-modulating nanoplatform provides a potent and safe therapeutic strategy for combating TNBC and preventing its metastasis, offering strong potential for clinical translation.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Yuzhen Zhao,Mingge Li,Yue Guo,Jian Jin,Fei Pei,Wenya Wang,Changhua Liu,Wenyan Yu,Jinjin Shi,Na Yin
Bacteria have shown great potential in anti-tumor treatment, and an attenuated strain of Salmonella named VNP20009 has been shown to be safe in clinical trials. However, colonized bacteria recruit neutrophils into the tumor, which release NETs to capture and eliminate bacteria, compromising bacterial-based tumor treatment. In this study, we report a neutrophil hitchhiking nanoparticles (SPPS) that block the formation of NET to enhance bacteria-mediated tumor therapy. In the 4 T1 tumor-bearing mouse model, following 24 h of bacterial therapy, there was an approximately 3.0-fold increase in the number of neutrophils in the bloodstream, while the amount of SPPS homing to tumor tissue through neutrophil hitchhiking increased approximately 2.0-fold. It is worth noting that the NETs in tumors significantly decreased by approximately 2.0-fold through an intracellular ROS scavenging-mediated NETosis reprogramming, thereby increasing bacterial vitality by 1.9-fold in tumors. More importantly, the gene drug (siBcl-2) loaded in SPPS can be re-encapsulated in apoptotic bodies by reprogramming neutrophils from NETosis to apoptosis, and enable the redelivery of drugs to tumor cells, further boosting the antitumor efficacy with a synergistic effect, resulting in about 98% tumor inhibition rate and 90% survival rate.
研究领域:
癌症治疗
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纳米技术
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免疫学
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分子生物学
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高影响因子
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