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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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Sen Chen,Hui Lin,Haodi Gu,Xinrou Yu,Junjie Xiang,Lili Xu,Gang Ye,Yue Shan,Yun Wang
Introduction Sepsis-induced cardiomyopathy (SIC) is a rapidly advancing condition associated with a poor prognosis due to the lack of effective treatments. Neutrophil extracellular traps (NETs), however, act as a double-edged sword in the innate immune response during sepsis. N-formyl methionine (fMet) has been documented to induce NETs in inflammatory conditions, yet its clinical significance and biological function in SIC remain unclear. In this study, we investigated whether fMet induces excessive NETs, thereby promoting SIC. Methods and results Clinically, serum fMet levels were quantified using ELISA, revealing a significant elevation in patients with SIC compared to non-sepsis patients and healthy controls. The fMet levels were positively correlated with the NETs-related markers myeloperoxidase (MPO) and double-stranded DNA (dsDNA) in patients with SIC. Treatment with lipopolysaccharide and fMet increased NET formation in human neutrophils and upregulated the expression of formyl peptide receptor 1 (FPR1) and hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, bone marrow-derived neutrophils (BMDNs) were isolated from global FPR1 knockout mice, and FPR1 deficiency in BMDNs was found to suppress NETosis. The cecal ligation and puncture (CLP) model was employed to induce SIC in mice and we found knockout of FPR1 improved outcomes in CLP mice, as evidenced by survival benefit, increased cardiac function, attenuated cytokine storm, reduced neutrophil infiltration, improved mitochondrial function and suppressed NETosis, compared with those of wild-type (WT) mice. In addition, treatment with FPR1 inhibitor HCH6–1 improved cardiac outcome and inhibits NETosis in CLP mice. Conclusion These data reveal the role of fMet-mediated FPR1/HIF-1α activation in promoting SIC through the NETosis, indicating novel therapeutic strategy for SIC.
研究领域:
免疫学
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心血管病学
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分子生物学
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重症医学
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炎症与感染
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信号转导
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转化医学
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DOI
PubMed
高影响因子
Regenerative Biomaterials
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2024
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IF 5.6
Xie Yinhong,Chi Mengchen,Yang Xinlei,Dong Ruichen,Yang Ao,Yin Antao,Weng Yajun
Modification of polylactic acid (PLA) is a promising strategy for the next generation of bioresorbable vascular stent biomaterials. With this focus, FeMOFs nanoparticles was incorporated in PLA, and then post loading of CO was performed by pressurization. It showed FeMOFs incorporation increased hydrophilicity of the surface and CO loading, and CO release was sustained at least for 3d. It is well acknowledged NETosis and macrophage mediated inflammation are the principal effectors of atherosclerosis and cardiovascular disease, and it further increases the risk of late stent thrombosis and restenosis. In this study, the effects of CO release of PLA/FeMOFs/CO on NETosis and macrophage behavior were thoroughly explored. In vitro evaluation results showed that PLA/FeMOFs/CO significantly inhibited neutrophil extracellular traps (NETs) release and neutrophil elastase (NE) expression by reducing intracellular ROS in a simulated inflammatory environment. It reduced LPS-induced macrophage inflammation with decreased TNF-α expression and increased IL-10 expression. Meanwhile it enhanced endothelial cell activity and growth in inflammatory environment, and inhibited platelet adhesion and activation. In vivo implantation results confirmed that PLA/FeMOFs/CO reduced the macrophages and neutrophils mediated inflammatory response, thus reduced the neointimal hyperplasia. Overall, PLA/FeMOFs/CO effectively prevented the inflammation and restenosis associated with PLA implantation. Our study provides a new strategy to improve the immunocompatibility of PLA implant materials.
研究领域:
生物材料
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心血管工程
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免疫学
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组织工程
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DOI
PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Jia Li,Yangbo Xu,Congrui Zhao,Xiaoyu Chen,Chuchu Xu,Chuan Zhou,Hui Wang,Antian Xu,Fuming He
The innate immune response to bone biomaterials critically regulates osteogenesis, yet the molecular mechanisms governing neutrophil-macrophage crosstalk remain poorly understood. Building on our discovery of neutrophil involvement in bone regeneration, we investigated the E3 ubiquitin ligase-Tripartite motif containing protein 30a(TRIM30a) as a potential orchestrator of inflammatory resolution and osseointegration. Through integrated multi-omics analysis of pro-osteogenic versus non-osteogenic metallic implants, we identified TRIM30a as a key regulator. Using conditional knockout mice (whole-body, neutrophil-specific, and macrophage-specific TRIM30a deficiency) combined with NETosis assays and inflammatory signaling profiling, we systematically evaluated TRIM30a's role on NETosis/cGAS-STING axis in bone regeneration, with pharmacological validation using DNase I in murine femoral implant models. TRIM30a expression is positively correlated with the osteogenic ability of pro-osteogenic implants. Mechanistically, TRIM30a suppressed NF-κB/NLRP3 in neutrophils, while synergizing with NET-derived dsDNA to modulate cGAS-STING signaling in macrophages, achieving balanced cytokine production. Therapeutic intervention with DNase I rescued bone formation in TRIM30a-deficient mice, confirming the pathway's clinical relevance. Our work establishes TRIM30a as a master regulator of bone regeneration through dual mechanisms: restraining neutrophil hyperactivation via NF-κB/NLRP3 inhibition while cooperating with dsDNA to calibrate macrophage cGAS-STING signaling, revealing a targetable immunomodulatory axis for enhancing osseointegration. These findings provide new insights into the immune-bone regeneration interface and suggest novel therapeutic strategies for implant-related bone repair.
研究领域:
免疫学
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骨再生医学
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生物材料科学
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分子生物学
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炎症研究
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DOI
PubMed
高影响因子
ADVANCED MATERIALS
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2026
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IF 26.8
Jiaying Lin,Jiali Duan,Jiangna Guo,Hui Xu,Rongwei Shi,Linhui Zhao,Yangyang Liu,Na Meng,Jiateng Zhou,Xiao Zhang,Shihui Lin,Feng Yan,Bin Wang,Hailei Mao
Staphylococcus aureus membrane vesicles (MVs) cause host injury and excessive inflammation, yet their pathological roles and clearance strategies remain undefined. Guided by molecular dynamics simulations of MV-polymer interactions, we engineered imidazolium-based poly(ionic liquid) (PIL) electrospun nanofibers for targeted MV interception. Among multiple formulations, PIL-C4 demonstrated optimal performance, combining potent antibacterial activity, robust adsorption of methicillin-resistant S. aureus (MRSA) MVs and their virulence factors, minimal cytotoxicity, and inhibition of resistance transmission. In vivo, PIL-C4 attenuated MV-induced neutrophil extracellular trap (NET) formation (NETosis) and vascular leakage, thereby reducing purulent-exudative wound injury and preventing systemic organ damage, including fatal lung injury. Notably, DNase-mediated NET degradation alone failed to rescue MV pathology, underscoring the necessity of direct MV clearance. This study uncovers previously unrecognized NETosis-driven phenotypes of S. aureus MVs—local purulent-exudative wound injury and systemic lethal lung damage—and establishes a polymer-based clearance strategy with translational potential for infection control.
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DOI
PubMed
高影响因子
Materials Today Bio
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2026
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IF 11
Yu He,Xiaoqi Yang,Yongke Bai,Xiaozhuo Ba,Tao Ye,Zichen Zhong,Zhiqiang Chen,Heng Li,Kun Tang
Calcium oxalate (CaOx) nephrocalcinosis is a chronic kidney disease marked by CaOx crystal deposition, oxidative stress, neutrophil infiltration, and renal tubular epithelial cell injury. To date, no targeted therapies are clinically available for this condition. Antioxidant nanomaterials capable of scavenging excessive reactive oxygen species (ROS) offer a promising approach for treating CaOx crystal-induced kidney injury. Neutrophil-mediated delivery systems have been leveraged to transport nanomaterials to inflamed kidneys for acute kidney injury therapy, and their targeting specificity can be further augmented through the functionalization of cell membranes with targeting peptides. Herein, we developed a biomimetic nanoplatform by loading DNase I onto black phosphorus nanosheets (BPNSs) and coating them with a neutrophil membrane modified with a CD44-targeting peptide (PNM@D@BP), aiming to ameliorate renal CaOx crystal deposition and the consequent kidney injury. The engineered neutrophil membrane coating conferred the nanocarrier with the ability to home to sites of renal injury and inflammation. PNM@D@BP exhibited potent antioxidative activity, effectively eliminating CaOx crystal-induced ROS. In both in vivo and in vitro settings, PNM@D@BP was shown to suppress the formation of neutrophil extracellular traps (NETs). Moreover, RNA sequencing and bioinformatic analyses revealed that PNM@D@BP protects against CaOx crystal-induced kidney injury by modulating oxidative stress and neutrophil-driven inflammatory responses. Collectively, these findings underscore the therapeutic potential of PNM@D@BP for the treatment of CaOx kidney stones.
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
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2026
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IF 4.9
Xin Liu,Yun Liu,Wuqi Guo,Xinghua Li,Yiran Han,Qiang Huo,Yang Liu,Yimin Niu
The activation, adhesion, and migration of neutrophils are one of the main reasons for the progression of acute lung injury (ALI) and a new therapeutic target for ALI. Although respiratory administration for ALI has the characteristics of targeted drug delivery, some issues, such as the drug’s short residence time in the lungs, rapid clearance rate, and lack of specificity for neutrophils, make it difficult to maintain an effective drug concentration. Here, we designed and evaluated a neutrophil-targeting peptide NEBP-modified andrographolide liposome (N-Lip@A) that can be administered via the respiratory tract to inhibit the formation of neutrophil extracellular traps, aiming to provide a rapid, efficient, and precise intervention strategy for ALI. N-Lip@A liposomes were synthesized by the traditional thin-film hydration method. Cell immunofluorescence and scanning electron microscopy observations indicated that N-Lip@A could reduce the formation of neutrophil extracellular traps (NETs). Quantitative analysis using the PicoGreen assay showed that the release of double-stranded DNA (dsDNA) in the N-Lip@A group was reduced to 57.9% compared with the untreated PMA group, and its effect was superior to that of the nontargeted liposome formulation (Lip@A). SYTOX staining, CCK8 assay, and Calcein-AM/PI staining results demonstrated that N-Lip@A could reduce the death of PMA-stimulated neutrophils. Besides, compared with the untreated group, the supernatant from neutrophils pretreated with N-Lip@A increased the survival rate of alveolar epithelial MLE-12 cells. In a lipopolysaccharide-induced murine model of ALI, compared with the nontargeted Lip@A group or the untreated group, the pathological lung injury score decreased to 52.6% and 31.6%, respectively. Significant disease remission, including reduced pulmonary edema, restored integrity of the blood–air barrier, and improved alveolar architecture were also demonstrated through EB staining analysis, lung wet-to-dry weight ratio determination, and HE staining analysis. Collectively, N-Lip@A enables precise delivery of AGL to activated neutrophils via NEBP-mediated targeting, effectively inhibiting NETs formation and mitigating ALI-associated pathological damage. This strategy provides an expandable targeted drug delivery platform for the treatment of various acute or chronic pulmonary inflammatory diseases driven mainly by neutrophils.
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Xiaozhuo Ba,Xiaoqi Yang,Yu He,Tao Ye,Xiaoyong Zeng,ZiChen Zhong,XiaoLin Guo,Kun Tang
Kidney stones are among the most common renal diseases with high global incidence and recurrence rates, with calcium oxalate (CaOx) stones constituting 65.9% to 80% of all cases. Minimally invasive surgery remains the primary approach for kidney stones, while limited progress has been made in the drug therapy for CaOx kidney stones over the recent years. The limitations of traditional drug therapy, such as renal toxicity and poor targeting, along with an elusive pathogenesis of CaOx kidney stones, have prevented its widespread clinical application. Renal tubular epithelial cells injury has been reported to play a crucial role in the occurrence and development of CaOx kidney stones. Nanozymes with potent antioxidant and anti-inflammatory properties have the potential to treat CaOx crystal-induced kidney injury. Moreover, as a key stone inhibitor, potassium citrate is widely used to inhibit stone formation due to its ability to modify urinary chemistry. Herein, we designed citrate-coated Prussian blue nanozyme hitchhiking on the neutrophils (NM@CPBzyme) with injured kidney targeting capability and good biosafety. The results showed that NM@CPBzyme alleviated CaOx crystal-induced kidney injury and CaOx crystals deposition. On the one hand, NM@CPBzyme has been demonstrated to not only suppress oxidative stress but also chelate calcium ions, thereby facilitating crystal dissolution. On the other hand, NM@CPBzyme could mitigate neutrophil infiltration, NETosis and inhibit pyroptosis in vitro and in vivo. In addition, RNA sequencing and bioinformatic analysis further showed that NM@CPBzyme ameliorates CaOx crystal-induced kidney injury via oxidative stress and neutrophil mediated inflammatory response. In summary, our results revealed that NM@CPBzyme is a novel strategy for protecting against CaOx crystal-induced kidney injury.
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产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
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2026
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IF 6.3
Yang Liu,Yan Lu,Weilian Bao,Haiyan Zhu,Guoqi Yuan,Linfeng Guo,Hong Li,Jiyang Li,Tong Wu,Xunlong Shi,Daofeng Chen
Secondary bacterial infection is a major cause of severe progression and death in viral pneumonia. The excessive recruitment of neutrophils accompanied by the formation of neutrophil extracellular traps (NETs) plays an important role in excessive inflammation caused by viral-bacterial co-infection, but effective pharmacological interventions remain lacking. Our study revealed that quercitrin (QTN), a flavonoid commonly found in traditional Chinese medicine and daily diets, significantly reduced mortality, recruitment of neutrophils, the production of inflammatory cytokines, and viral and bacterial loads in H1N1 influenza and methicillin-resistant Staphylococcus aureus (MRSA) coinfection-induced pneumonia in mice. Mechanistically, QTN down-regulates the interaction between Histone H3 and myeloperoxidase (MPO), thereby mitigating excessive inflammation induced by NETs. Our study demonstrates that inhibiting NETosis with QTN is one of the effective strategies for co-infection treatment.
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产品关联
DOI
PubMed
高影响因子
ONCOGENE
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2026
·
IF 9.1
Liu Pengpeng,Wang Huizhen,Yu Kexun,Ma Mengdi,Yang Xiongwei,Wang Yuexiang,Li Yongxiang
Lymphangiogenesis drives gastric cancer lymph node (GC LN) metastasis via neuro-immune-cancer interactions in the tumor microenvironment. However, the underlying mechanisms remain incompletely understood. Here, we demonstrate that chronic stress (CS) in GC patients correlates with poorer short-term prognosis, perineural/lymphovascular invasion, and advanced LN staging. Mechanistically, CS-induced neutrophil extracellular traps (NETs) are key mediators of LN metastasis. Inhibiting NETs suppressed popliteal LN metastasis and lymphangiogenesis. In vitro and in vivo experiments revealed that CS upregulated acetylcholine (ACh) and choline acetyltransferase (ChAT) levels, with ACh directly inducing NETs formation in a dose-dependently. Exogenous ACh increased LN metastasis (volume), whereas gastric vagotomy attenuated CS-mediated orthotopic tumor growth. Functional assays confirmed that ACh-driven NETs enhanced GC cell malignant behaviors, accelerated adhesive suspension state transformation via extracellular matrix remodeling, and activated a feedforward ACh-NGF axis. This triggered PKC-γ/STAT3-S100A8/A9-ROS cascade, mediating NETs formation and upregulating VEGFA/C. Protein analysis showed CD300ld overexpression in CS + GC tissues, independent of ACh signaling. Notably, combined targeting of the NGF/TrkA and CD300ld exerted synergistic anti-LN metastatic and lymphangiogenic effects. Collectively, this study elucidates a CS-driven mechanism regulating NETs to promote GC LN metastasis and identifies NGF/TrkA and CD300ld as therapeutic targets for GC LN metastasis.
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Shu-Zhen Dai,Ri-Hong Wu,Hengyu Chen,Ming-Hui Chen,Weijing Xie,Wu-Ping Zheng,Guang-Hong Tan,Feng-Ying Huang
Background The process of NETosis is observed in a range of inflammatory conditions. Progesterone (P4) has been shown to alleviate inflammation caused by viral infections such as influenza and SARS-CoV-2. However, the precise molecular mechanisms responsible for this effect are not yet fully understood. Therefore, the present investigation aims to explore whether P4 can exert its anti-inflammatory properties by inhibiting NETosis and the related molecular pathways. Methods Airway inflammation caused by rhinovirus serotype-1b (RV-1b) was induced in male BALB/c mice. The inflammation was assessed through histological examination and calculation of inflammatory cells present in the bronchoalveolar lavage fluid. Flow cytometry was used to analyze the inflammatory cells and NETotic neutrophils. Western blotting analysis was conducted to detect proteins associated with NETosis, inflammasome activation, and signaling. Furthermore, confocal microscopy was utilized to observe neutrophil extracellular trap (NET) structures in vivo tissues and in vitro neutrophils, neutrophil infiltration, and inflammasome formation. Results The administration of P4 proved to be an effective treatment for reducing airway inflammation and the production of NETs caused by RV-1b infection. The infection triggered the activation of NLRP3 inflammasomes in neutrophils, which led to the maturation of IL-1β and subsequent activation of both the NF-κB and p38 signaling pathways. The activation of NF-κB signaling resulted in the secretion of downstream chemokines CCL3 and IL-6, which led to an increase in neutrophil infiltration into the lung airways. Moreover, the activation of p38 signaling led to the generation of reactive oxygen species, resulting in NETosis. However, the administration of P4 inhibited the activation of the NLRP3 inflammasome, which subsequently led to the deactivation of both the IL-1β-NF-κB and IL-1β-p38 axes. As a result, there was a reduction in neutrophil infiltration and NETosis. Furthermore, TGF-β-activated kinase 1 (TAK1) was identified as an intermediary enzyme. P4 inhibits both the NF-κB and IL-1β-p38 pathways by suppressing the activity of TAK1. Conclusion The capacity of P4 to mitigate rhinovirus-induced airway inflammation is attributed to its ability to impede the infiltration of neutrophils and NETosis. As inflammation mediated by NETosis is widespread in diverse disorders, our findings propose that P4 could potentially function as a universal therapeutic agent in the management of such ailments.
研究领域:
免疫学
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呼吸病学
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病毒学
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药理学
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产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2026
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IF 16.2
Jiani Gao,Ke Zhou,Yijiu Ren,Fengjing Yang,Minjue Shan,Yubing Fang,Changbo Sun,Weili Han,Chang Chen,Xuefei Hu
Transfusion-related acute lung injury (TRALI) remains a life-threatening complication of blood transfusion, yet the macrophage-neutrophil-NETosis inflammatory amplification mechanism and effective interventions are still incompletely defined. Here, we examined a CD36/Fyn-CXCL-related axis in TRALI and evaluated a ROS-responsive platelet extracellular vesicle biomimetic nanosystem (PEV@SP@EG) as a targeted delivery strategy. In a murine TRALI model, exploratory single-cell transcriptomic analysis showed immune-cell remodeling and linked CD36 expression to M1-like macrophage features. CD36 knockdown or pharmacological inhibition of Fyn/NF-kappaB reduced M1 polarization markers, CXCL production, and ROS generation. Conditioned medium from CD36-overexpressing BMDMs promoted neutrophil migration and NETosis, whereas CXCL-CXCR2 blockade or CD36/Fyn inhibition weakened these responses. PEV@SP@EG showed ROS-triggered drug release and preferential lung enrichment. In vivo , PEV@SP@EG attenuated CD36/Fyn-NF-kappaB-CXCL-related inflammatory signaling, NET formation, and oxidative stress in TRALI lung tissue, with concomitant improvement in lung architecture and gas exchange. These findings support a role for macrophage CD36/Fyn signaling in TRALI-associated macrophage-neutrophil inflammatory crosstalk and suggest that PEV@SP@EG may provide a targeted nanotherapeutic delivery platform for TRALI intervention.
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高影响因子
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