ACS Nano
·
2025
·
IF 16
Xiaotong Chen,Lei Lei,Jiayao Yan,Xingzhou Wang,Lin Li,Qin Liu,Ying Wang,Tianran Chen,Jie Shao,Lixia Yu,Zijian Li,Lijing Zhu,Lifeng Wang,Baorui Liu
Although personalized neoantigen cancer vaccines have emerged as a promising strategy for cancer treatment, challenges remain to develop immune-stimulatory carriers which allow simultaneous transport of adjuvants and vaccines to lymph nodes (LNs). With inherent immunogenicity, genetic plasticity, and efficiency for large-scale production, M13 phages represent an attractive platform for vaccine delivery as natural bionanomaterials. Here, we report the discovery of an anti-CD40 designed ankyrin repeat protein (DARPin) and propose a bifunctional M13 ph age for neoantigen delivery based on this anti-CD40 DARPin protein (M13CD40). M13CD40-based neoantigen vaccines show improved accumulation and prolonged antigen retention in LNs compared with nontargeting phage vaccines due to the abundance of CD40-positive cells in LNs. Besides the intrinsic immunogenicity of phages, M13CD40-based neoantigen vaccines also benefit from additional CD40 stimulation due to multiple copies of anti-CD40 DARPins displayed on M13CD40 phages. Subcutaneous immunization with M13CD40-based neoantigen vaccines results in more robust antigen-specific immune responses and superior antitumor efficacy in poorly immunogenic tumor models compared with nontargeting phage vaccines. Combination therapy with PD-1 blockade further enhances T cell cytotoxicity and improves tumor control. To summarize, our findings highlight M13CD40 as a CD40 nanoagonist as well as an efficient vehicle for LN-targeted delivery of personalized neoantigen vaccines.
研究领域:
肿瘤学
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免疫学
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纳米医学
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DOI
PubMed
高影响因子
Small Methods
·
2023
·Vol. 7
·期 3
·2200925
·
IF 12.4
Tianliang Fang,Baoqi Li,Meng Li,Yuli Zhang,Zhangyan Jing,Yuan Li,Tianyuan Xue,Zhirang Zhang,Wenli Fang,Zhongda Lin,Fanqiang Meng,Liyan Li,Yang Yang,Xingding Zhang,Xin Liang,Shu-Na Chen,Jun Chen,Xudong Zhang
Immune intervention of B cell activation to blockade the production of autoantibodies provokes intense interest in the field of systemic lupus erythematosus (SLE) therapy development. Although the survival rate for SLE is improved, many patients die untimely. Engineered cell membrane vesicles manifest remarkable capacity of targeted drug delivery and immunomodulation of immune cells such as B cells. Herein, this work engineered cellular nanovesicles (NVs) presenting CD40 (CD40 NVs) that can blunt B cells and thus alleviate SLE. CD40 NVs disrupt the CD40/CD40 ligand (CD40L) costimulatory signal axis through the blockade of CD40L on CD4 + T cells. Therefore, the CD40 NVs restrain the generation of the germinal center structure and production of antibodies from B cells. Furthermore, immunosuppressive drug mycophenolate mofetil (MMF) is also encapsulated in the vesicles (MMF-CD40 NVs), which is employed to deplete immunocytes including B cells, T cells, and dendritic cells. Together, CD40 NVs are promising formulations for relieving autoimmunity and lupus nephritis in MRL/lpr mice.
研究领域:
免疫学
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药学
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生物技术
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DOI
PubMed
高影响因子
Biomedical Materials
·
2024
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IF 3.9
Chen Huang,Wentao Huang,Yixuan Meng,Chengqian Zhou,Xiaozhuan Wang,Chunyu Zhang,Yuzhen Tian,Wei Wei,Yongsheng Li,Quan Zhou,Yukuan Tang,Wenli Chen
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of cholesterol within the arterial wall. Its progression can be monitored via magnetic resonance imaging (MRI). Ultrasmall Superparamagnetic Particles of Iron Oxide (USPIO) (<5 nm) have been employed as T1 contrast agents for MRI applications. In this study, we synthesized USPIO with an average surface carboxylation of approximately 5.28 nm and a Zeta potential of -47.8 mV. These particles were phagocytosed by mouse aortic endothelial cells (USPIO-MAECs) and endothelial progenitor cells (USPIO-EPCs), suggesting that they can be utilized as potential contrast agent and delivery vehicle for the early detection of atherosclerosis. However, the mechanism by which this contrast agent is delivered to the plaque remains undetermined. Our results demonstrated that with increasing USPIO concentration during 10-100 μg/mL, consistent change appeared in signal enhancement on T1-weighted MRI. Similarly, T1-weighted MRI of MAECs and EPCs treated with these concentra-tions exhibited a regular change in signal enhancement. Prussian blue staining of USPIO revealed substantial absorption into MAECs and EPCs after treatment with 50 μg/mL USPIO for 24 h. The iron content in USPIO-EPCs was much higher (5 pg Fe/cell) than in USPIO-MAECs (0.8 pg Fe/cell). Our results confirmed that macrophages are more likely to bind to MAECs treated with AuNPs-PEI-siRNANC (control) for 72 h than to MAECs treated with AuNPs-PEI-siRNACD40 (reduced CD40 expression), thus confirming CD40 targeting at the cellular level. When USPIO-MAECs and MAECs (control) were delivered to mice (high-fat-fed) via tail vein injection respectively, we observed a higher iron accumulation in plaques on blood vessels in high-fat-fed mice treated with USPIO-MAECs. We also demonstrated that USPIO-EPCs, when delivered to high-fat-fed mice via tail vein injection, could indeed label plaques by generating higher T1-weighted MRI signals 72 h post injection compared to controls (PBS, USPIO and EPCs alone).
In conclusion, we synthesized a USPIO suitable for T1-weighted MRI. Our results have confirmed separately at the cellular and tissue and in vivo level, that USPIO-MAECs or USPIO-EPCs are more accessible to atherosclerotic plaques in a mouse model. Furthermore, the high expression of CD40 on the cell surface is a key factor for targeting and USPIO-EPCs may have potential therapeutic effects.
研究领域:
医学影像
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心血管疾病
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分子生物学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2015
·
IF 6.409
Guolin Yuan,Chao Yu,Chunyong Xia,Liuliu Gao,Wailan Xu,Wenjuan Li,Junlin He
A simplified electrochemical multianalyte immunosensor for the simultaneous detection of high sensitivity C-reactive protein (hsCRP) and soluble CD40 ligand (sCD40L) that uses reduced graphene oxide-tetraethylene pentamine (rGO-TEPA) that directly adsorbs metal ions as labels is reported. rGO-TEPA contains a large number of amino groups and has excellent conductivity , making it an ideal template for the loading of Pb 2+ and Cu 2+ , which greatly amplifies the detection signals. The signals could be directly detected in a single run through differential pulse voltammetry (DPV), and each biorecognition event produces a distinct voltammetric peak. The position and size of each peak reflects the identity and the level of the corresponding antigen. Primarily designed for an application in a sandwich-type immunoassay based on Pb 2+ and Cu 2+ labels, two main challenges are accomplished with the herein presented nanosheets : fabrication of the template and the amination process for Pb 2+ and Cu 2+ adsorption. To further improve the analytical performance of the immunosensor, [email protected] serum albumin (BSA) nanospheres synthesized through a “green” synthesis route were used as a sensor platform, which not only provides a biocompatible microenvironment for the immobilization of antibodies but also amplifies the electrochemical signals. Under optimal conditions, hsCRP and sCD40L could be assayed in the range of 0.05 to 100 ng mL −1 with detection limits of 16.7 and 13.1 pg mL −1 ( S / N =3), respectively. The assay results on clinical serum samples with the proposed immunosensor were in acceptable agreement with those using the standard single-analyte test of the enzyme-linked immunosorbent assay (ELISA). This novel immunosensing system provides a simple, sensitive and low-cost approach for a multianalyte immunoassay.
研究领域:
生物医学工程
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分析化学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2023
·
IF 5.9
Honghong Feng,Yangjing Zhao,Yeping Li,Xueyong Qi,Song Shen,Shengwang Zhou
Nanotechnology provides the platform to develop functional nanocomposites with outstanding features, such as persistent luminescence (PL), photothermal conversion, magnetic resonance (MR), and so on, that has been incorporated in nanomedicine for diagnosis and therapy. Herein, the nanocomposites of ZnGa2O4:Cr3+ embedded in mesoporous silica coating surrounding gold nanorods (cGNR@MSNs) were developed for the codelivery of chemotherapeutic drugs and anti-CD40 antibodies. The nanocomposites were functionalized with tetrazaheterocycle linking divinylpyrimidine derivatives (DOTVs), which covalently capture anti-CD40 by disulfide re-bridging on the surface of cGNR@MSNs. The anti-CD40-mediated dual drug delivery system simultaneously realized the combination of chemo-, immuno-, and photothermal therapies, enhancing the synergistic effect of combination therapy for multiple tumor cells. Moreover, the nanodrug delivery system achieved multimodality imaging with fluorescence, PL, and MR modes for precise diagnosis. This study provides fascinating insights into the development of nanocomposite-based multimodality imaging strategies and imaging-guided combination therapies.
研究领域:
纳米技术
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纳米医学
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癌症治疗
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成像技术
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产品关联
DOI
高影响因子
Microbiome
·
2026
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IF 14.9
Fu Yang,Yin Nuoming,Huang Zehua,Qin Wenfei,Xu Binqiang,Huang Huizhen,Hu Jia,Cui Mengyan,Mei Qixiang,Fan Junjie,Lu Yingying,Jiang Qiaoli,Hu Junjie,Huang Chunlan,Zeng Yue
Background Gut barrier dysfunction is critical in the pathogenesis of acute pancreatitis (AP), yet the underlying mechanisms remain unclear. Mucin 2 (MUC2), the primary component of the intestinal mucus layer, is essential for gut homeostasis and microbial eubiosis. This study aimed to elucidate the protective mechanism of intestinal MUC2 in AP. Results We reported that intestinal MUC2 expression was decreased in AP patients and correlated with disease severity. Intestinal epithelial-specific Muc2 knockout ( Muc2 ΔIEC ) mice demonstrated exacerbated AP in a gut microbiota-dependent manner. Decreased abundance of Lactobacillus and correlated reduced levels of riboflavin were found in Muc2 ΔIEC mice after AP induction. Supplementation with riboflavin effectively ameliorated AP in Muc2 ΔIEC mice, whereas administration of an engineered strain deficient in riboflavin synthesis failed to provide a protective effect. MUC2 deficiency aggravated a macrophage-dominant immune imbalance in the pancreas, which was reversed by riboflavin. In vitro experiments revealed that riboflavin suppresses pro-inflammatory macrophage activation by inhibiting the CD40 signaling pathway. This inhibition preserved mitochondrial function and reversed the histone H3 acetylation at pro-inflammatory gene promoters. Conclusion Our study demonstrates that intestinal MUC2 deficiency is associated with reduced levels of microbiota-derived riboflavin, which could partially suppress pro-inflammatory macrophage activation via the CD40 pathway. Targeting the microbiota-derived riboflavin in AP may help to ameliorate the disease course.
Video Graphical
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DOI
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Huang Yaxian,Wu Jinyan,Zhan Chi,Liu Rong,Zhou Zhaocai,Huang Xin,Tian Yaguang,Lin Zhengmei,Song Zhi
The enhanced osteoclastogenesis contributes to alveolar bone resorption in periodontitis, which increases the risk of tooth loss. To reduce bone destruction, the inhibition of osteoclast development is proposed as a feasible treatment. CD40L-CD40-TRAF6 signal transduction plays a crucial role in inflammation, but how it regulates osteoclast activity in periodontitis has not been elucidated. In this study, we showed the potential role of CD40L-CD40-TRAF6 signaling in periodontitis. CD40L obviously promoted osteoclast formation and bone resorption capacity in vitro. Mechanistically, we found that osteoclastogenesis was enhanced by the overexpression of NFATc1 and NF-κB activation. Importantly, osteoclast activity was effectively suppressed by TRAF-STOP, a small molecular inhibitor of TRAF6. Furthermore, local injection of TRAF-STOP-loaded injectable PLGA-PEG-PLGA hydrogel could alleviate ligation-induced periodontitis in vivo. Taken together, TRAF-STOP shows promising clinical efficacy in periodontitis through alleviating osteoclastogenesis.
研究领域:
牙科学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2023
·Vol. 35
·期 13
·2208923
·
IF 29.4
Yuanke Li,Haoqi Zhang,Ruikun Wang,Yuan Wang,Ruonan Li,Mingsheng Zhu,Xiangyun Zhang,Zhen Zhao,Yajuan Wan,Jie Zhuang,Hongkai Zhang,Xinglu Huang
Despite the promise in whole-tumor cell vaccines, a key challenge is to overcome the lack of costimulatory signals. Here, agonistic-antibody-boosted tumor cell nanovaccines are reported by genetically engineered antibody-anchored membrane (AAM) technology, capable of effectively activating costimulatory pathways. Specifically, the AAM can be stably constructed following genetic engineering of tumor cell membranes with anti-CD40 single chain variable fragment (scFv), an agonistic antibody to induce costimulatory signals. The nanovaccines are versatilely designed and obtained based on the anti-CD40 scFv-anchored membrane and nanotechnology. Following vaccination, the anti-CD40 scFv-anchored membrane nanovaccine (Nano-AAM/CD40) significantly facilitates dendritic cell maturation in CD40-humanized transgenic mice and subsequent adaptive immune responses. Compared to membrane-based nanovaccines alone, the enhanced antitumor efficacy in both “hot” and “cold” tumor models of the Nano-AAM/CD40 demonstrates the importance of agonistic antibodies in development of tumor-cell-based vaccines. To expand the design of nanovaccines, further incorporation of cell lysates into the Nano-AAM/CD40 to conceptually construct tumor cell-like nanovaccines results in boosted immune responses and improved antitumor efficacy against malignant tumors inoculated into CD40-humanized transgenic mice. Overall, this genetically engineered AAM technology provides a versatile design of nanovaccines by incorporation of tumor-cell-based components and agonistic antibodies of costimulatory immune checkpoints.
研究领域:
癌症免疫治疗
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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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生物医学工程
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DOI
PubMed
高影响因子
ONCOGENE
·
2024
·
IF 6.9
Meng Hui,Li Ling,Nan Manman,Ding Yi,Li Yizhen,Zhang Mingzhi
Dendritic cells (DCs) are critical mediators of antigen priming and T-cell activation. Zymogen granule protein 16 (ZG16) is demonstrated as an anti-oncogene in T-cell mediated antitumor immunity, but its effect on DCs is largely unknown. Herein, we wonder whether ZG16 affects the activation of DCs in pancreatic cancer. Firstly, the increased ZG16 expression was observed during the maturation of DCs derived from mouse bone marrow or human peripheral blood. Then, overexpression of ZG16 or exogenous introduction of recombinant ZG16 protein induced the expression of MHC II, CD86, CD84, and CCR7 on the surface of DCs, thereby facilitating the secretion of proinflammatory mediators IL-1β, IL-6, TNF-α, and IL-12/p70, supporting the promoting effect of ZG16 on DC maturation. By establishing the subcutaneous and orthotopic mouse models of pancreatic cancer, we confirmed that intraperitoneal injection of recombinant ZG16 protein (Re-mZG16) could induce tumor regression by stimulating DC maturation and enhancing antitumor responses of CD4 + , CD8 + , PD-1 + , and Ctla4+ cells. Besides, Re-mZG16 in combination with gemcitabine showed a synergistic effect in the treatment of pancreatic cancer. Mechanistically, we demonstrated that ZG16 inhibited the ubiquitination and degradation of CD40, which depended on the lectin domain of ZG16. In conclusion, this study provided a novel insight into the role of ZG16-CD40 axis in DC-based immunotherapy for pancreatic cancer.
研究领域:
免疫学
·
肿瘤学
·
癌症免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Anna Gan,Jinyu Wang,Dehong Zhang,Min Xie,Bo Wu,Tingxu Yan,Ying Jia
Background Acute lung injury (ALI) is a severe pulmonary condition characterized by inflammation and damage to the epithelial barrier of the lungs. Sanzi Yangqin Decoction (SZYQ) is a traditional therapeutic formula for lung diseases and has been shown to play a role in the regulation of ALI; however, the specific mechanisms by which it modulates the epithelial barrier remain unclear. Purpose This study aims to elucidate the specific mechanisms by which SZYQ regulates epithelial barrier injury in ALI. Methods We first identified the constituents for SZYQ in plasma through UHPLC-QTOF-MS. Subsequently, we utilized the GEO database in conjunction with network pharmacology to predict the mechanism by which SZYQ regulates epithelial barrier damage in ALI. An in vitro ALI epithelial barrier injury model was established using LPS-induced MLE-12 cells to evaluate the efficacy and mechanism of SZYQ. Additionally, an in vivo ALI model was created through intranasal LPS administration to validate the in vitro findings. To explore the key target, PCR array analysis was conducted on lung tissues, revealing that SZYQ functions by regulating CD40 in alveolar macrophages (AMs). Following this, clodronate liposomes were employed for AMs depletion, and CD40 ligand (CD40L) stimulation of MH-S and MLE-12 cells co-culture was utilized to verify the pharmacological effects of SZYQ both in vivo and in vitro. Results This study identified a total of 18 constituents for SZYQ in plasma. GEO database analysis results suggest that SZYQ may alleviate epithelial barrier damage in ALI by exerting anti-necroptotic effects. Both in vitro and in vivo results indicated that SZYQ inhibits the expression of key necroptosis proteins RIP1, RIP3, and MLKL, alleviates DRP1-mediated mitochondrial fission, regulates ROS and Ca 2+ release, promotes the proliferation and differentiation of type II alveolar epithelial cells (AT2), and thereby mitigates epithelial barrier damage in ALI. Following the depletion of AMs in vivo , the necroptosis of AT2, mitochondrial fission, and lung epithelial barrier injury in ALI mice were exacerbated; while the regulatory capacity of SZYQ on these factors was diminished. The co-culture experiments involving MH-S cells and MLE-12 cells demonstrated that SZYQ exerts an anti-necroptotic effect on AT2 by inhibiting the expression of CD40 on AMs. Additionally, SZYQ improved epithelial barrier function by promoting the proliferation and differentiation of AT2. Conclusions SZYQ improved epithelial barrier function in ALI by mediating the CD40 of AMs. Its mechanism of action involved inhibiting necroptosis in AT2, alleviating mitochondrial fission, and promoting the proliferation and differentiation of AT2.
研究领域:
中医中药
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呼吸病学
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药理学
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分子生物学
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炎症研究
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细胞死亡机制
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2023
·
IF 3.9
Yan Nan,Wang Zhengdong,Li Zhou,Zheng Yang,Chang Nan,Xu Kangjie,Wang Qian,Duan Xiaoxu
This study aimed to examine the immuntoxic effects of arsenic in the nervous system. Our results showed that arsenic increased corticocerebral and hippocampal weights ( p < 0.05). Morris water maze tests revealed that arsenic significantly increased the time spent in latency to platform on the fourth day in 50 mg/L arsenic exposure and the fifth day in 25 and 50 mg/L arsenic exposure, as well as reduced the path length in target quadrant, time spent in target quadrant, and crossing times of the platform ( p < 0.05). Hematoxylin–eosin staining showed that the vacuolated degeneration and pyknosis was found in the cerebral cortex and hippocampus of arsenic-treated mice. The mRNA levels of corticocerebral and hippocampal brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were decreased in the 50 mg/L arsenic-treated group ( p < 0.05). In addition, immunofluorescence staining showed that 25 and 50 mg/L arsenic all increased the expression of CD11b and glial fibrillary acidic protein (GFAP) in the cerebral cortex and hippocampus ( p < 0.05). Arsenic markedly raised antigen-presenting molecule MHCII and CD40 mRNA levels in the cerebral cortex and hippocampus and upregulated the cell chemokine receptor 5 (CCR5) and CCR7 mRNA levels in the cerebral cortex at the 50 mg/L arsenic group, and increased the CCR7 mRNA levels in the hippocampus at the 25 and 50 mg/L arsenic groups ( p < 0.05). Arsenic activated the nucleotide-binding domain-like receptor protein-3 (NLRP3) inflammasome, and enhanced its upstream promoter NF-κB protein level and downstream regulators IL-18 mRNA levels. Collectively, these results provide new evidences for the neuro-immune toxicity of arsenic. Graphical abstract
研究领域:
神经毒理学
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免疫毒理学
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神经科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Kit-Leong Cheong,Xu-Ting Xie,Tao Zhou,Sathuvan Malairaj,Suresh Veeraperumal,Saiyi Zhong,Karsoon Tan
Ulcerative colitis is a chronic, spontaneous inflammatory bowel disease that primarily affects the colon. This study aimed to explore how Porphyra haitanensis porphyran (PHP) modulates the immune response and the associated mechanisms that alleviate dextran sulphate sodium-induced colitis in mice. Histological assessments via H&E staining and AB-PAS staining revealed that PHP intervention partially restored the number of goblet cells and improved intestinal mucosal function. Immunohistochemical and Western blot analyses of claudin-1, occludin, and MUC-2 demonstrated that PHP could repair the intestinal barrier and reduce colon damage by upregulating the expression of these proteins. PHP intervention was associated with a decrease in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokine expression. Moreover, the expression of proteins involved in intestinal immune homing, such as CCR-9, CCL-25, MAdCAM-1, and α4β7, was significantly suppressed in response to PHP treatment. Conversely, PHP upregulates the expression of CD40 and TGF-β1, both of these can promote healing and reduce inflammation in the gut lining. This study demonstrates that PHP can ameliorate ulcerative colitis by enhancing the intestinal barrier and modulating immune responses. These findings offer valuable insights into the potential utility of P. haitanensis as a promising natural product for managing ulcerative colitis.
研究领域:
免疫学
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胃肠病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）