Acta Biomaterialia
·
2025
·
IF 9.6
Pai Wang,Heshi Liu,Lei Guo,Yixin Tang,Tianwei Lan,Rui Zhou,Huiqing Xu,Lu Wang,Xue Wang,Baiqiao Chen,Yixing Wang,Siyuan Wang,Chang Liu,Jie Chen,Caina Xu,Quan Wang,Huayu Tian
Colorectal cancer (CRC) remains a major global health burden as the third most commonly diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. While combination chemotherapy and immune agonists hold potential to overcome tumor heterogeneity through multi-pathway modulation, their therapeutic efficacy remains limited by off-target drug distribution and immunosuppressive tumor microenvironment (TME). To address this, we developed a tumor-targeted chemo-immunotherapy platform by encapsulating irinotecan (CPT-11) and resiquimod (R848) in hyaluronic acid (HA) coated MIL-100(Fe) metal-organic frameworks (CRMH NPs), enabling CD44-mediated delivery and synergistic anti-tumor responses. The system enabled controlled drug release in the acidic TME, promoting immunogenic cell death (ICD), inducing the cGAS-STING pathway and activating immune cells. In vitro , CRMH NPs induced significant ICD, as evidenced by the release of damage-associated molecular patterns (DAMPs) like high mobility group box 1 (HMGB1) and calreticulin (CRT), and matured dendritic cells (DCs), which triggered by TLR7 agonist, enhancing immune responses. It also activated the cGAS-STING pathway, which could efficiently induce the targeted cells to produce type I interferon (IFN) and proinflammatory cytokines, thereby enhancing T cell activation and recruitment. In vivo , CRMH NPs significantly reduced tumor growth in CT26 mouse models, activated innate immune signaling, and increased immune cell infiltration, demonstrating superior anti-tumor effects compared to free drugs and other nanoparticle formulations. Furthermore, CRMH NPs upregulated PD-L1 expression on tumor cells, suggesting potential synergy with immune checkpoint blockade therapy. Combining CRMH NPs with anti-PD-L1 therapy enhanced anti-tumor immunity, particularly in distant tumors, highlighting a promising approach to overcoming immune evasion and achieving durable tumor regression. These findings supported CRMH NPs as a versatile and effective platform for chemo-immunotherapy in CRC. Statement of Significance Colorectal cancer (CRC) remains a major global health challenge with limited treatment efficacy due to tumor heterogeneity and immunosuppression. This study introduces a novel tumor-targeted nanoparticle platform, CRMH NPs, which co-deliver the chemotherapeutic drug irinotecan (CPT-11) and the immune agonist resiquimod (R848) using hyaluronic acid-coated MIL-100(Fe) metal-organic frameworks. CRMH NPs enhance drug delivery, induce immunogenic cell death, and activate the cGAS-STING pathway, synergizing chemotherapy and immunotherapy. Demonstrating superior tumor suppression and immune activation in preclinical models, this platform overcomes key limitations of current therapies, such as off-target effects and immune evasion. Its combination with anti-PD-L1 therapy further improves outcomes, offering a promising strategy for durable CRC treatment. This work advances nanomedicine and immuno-oncology, providing a transformative approach for cancer therapy.
研究领域:
纳米医学
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免疫治疗
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肿瘤学
·
药物递送
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生物化学
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药理学
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产品关联
DOI
PubMed
高影响因子
POULTRY SCIENCE
·
2023
·
IF 4.4
Huimin Lv,Peng Chen,Yang Wang,Lianbin Xu,Kai Zhang,Jinshan Zhao,Huawei Liu
ABSTRACT This study aimed to determine the effects of chlorogenic acid ( CGA ) on the growth performance, intestinal health, immune response, and mitochondrial DNA ( mtDNA )–cyclic GMP–AMP synthase ( cGAS )–stimulator of interferon genes ( STING ) signaling pathway in broilers under necrotic enteritis ( NE ) challenge. The 180 one-day-old male Cobb 500 broilers with similar body weight of 44.59 ± 1.39 g were randomly allocated into three groups. The groups were control diet (Control group), control diet + NE challenge (NE group), and control diet + 500 mg/kg CGA + NE challenge (NE + CGA group), with six replicates per treatment. All broilers except the Control group were given sporulated coccidian oocysts (day 14) and Clostridium perfringens (days 19-21) by oral gavage. Our findings showed that CGA improved the growth performance and intestinal morphology in broilers under NE challenge. CGA supplementation elevated the barrier function in broilers under NE challenge, which reflected in the decreased serum concentrations of D-lactate and diamine oxidase, and upregulated jejunal protein expression of occludin. CGA supplementation also improved the immune function, which reflected in the increased concentrations and gene expressions of anti-inflammatory factors, and decreased concentrations and gene expressions of pro-inflammatory factors. CGA supplementation further enhanced intestinal cell proliferation and differentiation, which manifested in the increased number of goblet cells and positive cells of proliferating cell nuclear antigen on days 28 and 42. Furthermore, CGA supplementation decreased the mtDNA (day 42) and mitochondrial reactive oxygen species levels (days 28 and 42), and increased the mitochondrial membrane potential (day 42) and mitochondrial complex Ⅰ (days 28 and 42) or Ⅲ (day 28) activity. Broilers challenged with NE had upregulated jejunal protein expressions of cGAS, phospho-TANK-binding kinase 1, and phospho-interferon regulatory factor 7 compared with the Control group, which were downregulated after CGA supplementation. In conclusion, dietary supplementation CGA could protect against intestinal inflammation and injury by reducing the leakage of mtDNA and inactivating the cGAS–STING signaling pathway in broilers under NE challenge.
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DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2023
·
IF 4.7
Haoye Li,Qingwen Yang,Haitong Wu,Jianying Guo,Zhaoxin Tang,Jianzhao Liao
Terbuthylazine (TBA), a triazine herbicide, is extensively employed in agriculture for its wide range of effectiveness. However, prolonged utilization of TBA can pose a potential hazard to animals and human health. Here, a total of 180 broiler chickens ( Gallus gallus ) were stochastically assigned to three groups (control group, 0.4 mg/kg TBA group, and 4 mg/kg TBA group) for investigating the impact of TBA on cardiotoxicity. The results revealed that TBA exposure resulted in pathological alterations in the myocardium . Moreover, TBA exposure activated cGAS-STING pathway and markedly elevated the mRNA and protein expression levels of innate immune response (cGAS, STING, TBK1, and IRF3) in myocardium. Additionally, NF-κB signal was also activated under TBA exposure, which was characterized by the increasing mRNA expression levels of NF-κB, IKKα and the protein expression levels of p-NF-κB/NF-κB, IKKα, p-IκBα/IκBα in the TBA treatment groups. Meanwhile, the expression of pro-inflammatory cytokines (TNF-α and IL-1β) were also significantly increased. In summary, our findings suggested that cGAS-STING/NF-κB pathway functionated in the innate immune response and inflammation in myocardium brought on by TBA exposure, which provided new insights into the TBA toxicology.
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PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Zishan Zeng,Yue Sun,Jingwen Jiang,Xiaoyu Xu,Huanxin Lin,Wanzhen Li,Dong Zheng,Yanjuan Huang,Chunshun Zhao
Gastric cancer constitutes a malignant neoplasm characterized by heightened invasiveness, posing significant global health threat. Inspired by the analysis that gastric cancer patients with Helicobacter pylori ( H. pylori ) infection have higher overall survival, whether H. pylori can be used as therapeutics agent and oral drug delivery system for gastric cancer. Hence, we constructed engineered H. pylori for gastric cancer treatment. A type Ⅱ H. pylori with low pathogenicity, were conjugated with photosensitizer to develop the engineered living bacteria NIR-triggered system (Hp-Ce6). Hp-Ce6 could maintain activity in stomach acid, quickly infiltrate through mucus layer and finally migrate to tumor region owing to the cell morphology and urease of H. pylori . H. pylori, accumulated in the tumor site, severed as vaccine to activate cGAS-STING pathway, and synergistically remodel the macrophages phenotype. Upon irradiation within stomach, Hp-Ce6 directly destroyed tumor cells via photodynamic effect inherited by Ce6, companied by inducing immunogenic tumor cell death. Additionally, Hp-Ce6 exhibited excellent biosafety with fecal elimination and minimal blood absorption. This work explores the feasibility and availability of H. pylori -based oral delivery platforms for gastric tumor and further provides enlightening strategy to utilize H. pylori invariably presented in the stomach as in-situ immunomodulator to enhance antitumor efficacy.
研究领域:
肿瘤学
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药学
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免疫学
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生物技术
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2022
·
IF 8.101
Shanlong Zhang,Li Kang,Xiaoxue Dai,Junlan Chen,Zhengtao Chen,Meixiang Wang,Huantong Jiang,Xin Wang,Suqin Bu,Xinyuan Liu,Guohui Zhang,Hua Tang
Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, autophagy, and pyroptosis. Manganese play an important role in innate immunity and antitumor immunity. Many manganese-based nanomaterials induce tumor cell death by catalyzing the production of reactive oxygen species (ROS) within the tumor. However, the exact underlying mechanisms remain unclear. As research on ferroptosis advances and its regulatory mechanisms in tumors continue to be refined, more evidence has suggested that triggering ferroptosis in tumor cells is an effective strategy for tumor treatment. In this study, we found that administration of MnCl 2 to tumor cells resulted in lipid peroxidation and increased the levels of mitochondrial ROS, consequently leading to ferroptosis. Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defence is a targetable vulnerability in cancer. We show that MnCl 2 downregulated DHODH expression in tumor cells, resulting in increased mitochondrial ROS and lipid peroxidation to induce ferroptosis. In addition, MnCl 2 enhanced the phosphorylation levels of STING, TBK1, and IRF3 and upregulated the expression of type-I interferon (IFN), produced by the cGAS–STING signaling pathway. When inhibiting the cGAS–STING signaling pathway or type-I IFN, DHODH expression was restored, reversing lipid peroxidation and ROS production and rescuing MnCl 2 -induced ferroptosis.. Knockout of IFNAR1 or overexpression of DHODH weakens the antitumor effect of MnCl 2 . Mechanistically, these results revealed that Manganese treatment-activated cGAS–STING signaling promote mitochondrial lipid peroxidation and ROS production by releasing type-I IFNs that reduce DHODH function and thereby inducing ferroptosis in tumor cells. This may provide a new strategy to complement existing antitumor treatment regimens.
研究领域:
癌症生物学
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免疫学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Shengnan Huang,Chenyang Zhou,Chengzhi Song,Xiali Zhu,Mingsan Miao,Chunming Li,Shaofeng Duan,Yurong Hu
Postoperative tumor recurrence remains a predominant cause of treatment failure. In this study, we developed an in situ injectable hydrogel, termed MPB-NO@DOX + ATRA gel, which was locally formed within the tumor resection cavity. The MPB-NO@DOX + ATRA gel was fabricated by mixing a thrombin solution, a fibrinogen solution containing all-trans retinoic acid (ATRA), and a Mn/NO-based immune nano-activator termed MPB-NO@DOX. ATRA promoted the differentiation of cancer stem cells, inhibited cancer cell migration, and affected the polarization of tumor-associated macrophages. The outer MnO 2 shell disintegrated due to its reaction with glutathione and hydrogen peroxide in the cytoplasm to release Mn 2+ and produce O 2 , resulting in the release of doxorubicin (DOX). The released DOX entered the nucleus and destroyed DNA, and the fragmented DNA cooperated with Mn 2+ to activate the cGAS-STING pathway and stimulate an anti-tumor immune response. In addition, when MPB-NO@DOX was exposed to 808 nm laser irradiation, the Fe-NO bond was broken to release NO, which downregulated the expression of PD-L1 on the surface of tumor cells and reversed the immunosuppressive tumor microenvironment. In conclusion, the MPB-NO@DOX + ATRA gel exhibited excellent anti-tumor efficacy. The results of this study demonstrated the great potential of in situ injectable hydrogels in preventing postoperative tumor recurrence.
研究领域:
肿瘤学
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生物材料学
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免疫学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Zheng Jia,Xinyao Zhou,Jingjing Liu,Xinqi De,Yifan Li,Zaixing Yang,Haoyuan Duan,Fang Wang,Junwei Ge
The use of biomimetic mineralization strategy is promising to solve the problem of poor stability and immune effect of subunit antigens. However, non-specifically inducing protein mineralization is still a challenge. we hypothesized that rhamnolipids with both protein and metal binding capacity could be used to develop more functional and biocompatible calcium mineralized nanoparticle (RMCP). The results show that rhamnolipids synergistically enhanced the mineralization of protein with manganese ions and improved 21 % the loading antigens of RMCP compared to manganese calcium phosphate nanoparticles. Transmission electron microscopy (TEM) and Dynamic Light Scattering (DLS) showed particle size of RMCP is 260 ± 12.1 nm with spherical morphology. In vitro experiments have shown that RMCP effectively activate immune cells through the cGAS-STING and NLRP3 pathways and demonstrated a higher level of cytokines in RAW264.7 Macrophages. In vivo, RMCP triggered an increased IgG titer with 16.5-fold IgG2a/IgG1 ratio compared to the aluminum adjuvant which improved the recovery status after challenge in mice. We used biological surfactants for the first time to enhance the biomimetic mineralization process of subunit antigen, which provides a new approach for constructing calcium-based biocompatible antigen delivery vectors, helping to develop a new generation of stable, efficient, and safe subunit vaccines.
研究领域:
免疫学
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纳米技术
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疫苗开发
·
生物材料
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产品关联
DOI
PubMed
高影响因子
Colloid and Interface Science Communications
·
2025
·
IF 4.7
Shouguang Wang,Xiaofei Zhang,Dunmin Zhuang,Lina Dong,Bo Li
Objective Breast cancer remains a global health challenge due to limitations of conventional therapies, such as drug resistance and systemic toxicity. This study aimed to develop a novel synergistic chemo-immunotherapy platform by constructing Mn 2+ -coordinated oxidized hyaluronic acid (OHA)-based nanoparticles co-loaded with phloretin (PHL) (OHA@Lys/PHL Mn 2+ ). Methods A nanosystem was engineered using oxidized hyaluronic acid (OHA) modified with lysine (Lys) to co-encapsulate PHL and Mn 2+ ions. The anti-tumor efficacy was evaluated in vitro (4 T-1 breast cancer cells) and in vivo (4 T-1 tumor-bearing mice), including assessments of proliferation inhibition, apoptosis induction, reactive oxygen species (ROS) accumulation, DNA damage, cGAS-STING pathway activation, and dendritic cell (DC) maturation. Combination therapy with cisplatin (CDDP) was also investigated. Results OHA@Lys/PHL Mn 2+ achieved 80.3 % cell viability inhibition on 4 T-1 cells. Combined with CDDP, it further suppressed proliferation, induced apoptosis, and enhanced ROS accumulation. Mechanistically, the nanosystem induced DNA double-strand damage and activated the cGAS-STING pathway. In vivo , OHA@Lys/PHL Mn 2+ monotherapy showed significant tumor inhibition (46.4 %, p < 0.001). Combination with CDDP achieved near-complete tumor suppression (86.7 % inhibition) and reduced lung metastasis. The in vivo mechanism results indicated that nanosystem triggered DNA damage, activated cGAS-STING signaling, and significantly promoted DC maturation (48.5 % vs. 28.2 % in controls). Conclusion This strategy offers a promising and clinically translatable approach for advanced breast cancer treatment.
研究领域:
纳米医学
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肿瘤学
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药学
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免疫治疗
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药物递送系统
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生物化学
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分子生物学
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产品关联
DOI
高影响因子
PLoS Pathogens
·
2023
·Vol. 19
·期 4
·e1011314
·
IF 6.7
Lin Lv,Li Chai,Jie Wang,Mengge Wang,Danhui Qin,Hui Song,Yue Fu,Chunyuan Zhao,Jihui Jia,Wei Zhao,Mutian Jia
Stimulator-of-interferon gene (STING) is a vital element of the innate immune system against DNA viruses. Optimal activation of STING is crucial for maintaining immune homeostasis and eliminating invading viruses, and the oligomerization of STING is an essential prerequisite for STING activation. However, the mechanism of cGAMP-induced STING oligomerization in ER remains unclear. Selenoproteins are crucial for various physiological processes. Here, we identified that the endoplasmic reticulum (ER)-located transmembrane selenoprotein K (SELENOK) was induced during virus infection and facilitated innate immune responses against herpes simplex virus-1 (HSV-1). Mechanistically, SELENOK interacts with STING in the ER and promotes STING oligomerization, which in turn promotes its translocation from the ER to the Golgi. Consequently, Selenok deficiency suppresses STING-dependent innate responses and facilitates viral replication in vivo . Thus, the control of STING activation by selenium-mediated SELENOK expression will be a priming therapeutic strategy for the treatment of STING-associated diseases.
Selenoproteins are crucial for various physiological processes. Most selenoproteins locate in the cytoplasm and regulate redox pathways to protect cells from oxidative stress. However, the potential roles of transmembrane selenoproteins are largely unknown. Here, we identified Selenoprotein K (SELENOK), an ER-located transmembrane selenoprotein, as a physiological enhancer of STING-dependent antiviral innate immunity. SELENOK is upregulated during viral infection and enhances STING oligomerization to facilitate the activation of the cGAS-STING pathway and suppress viral replication. These results will be valuable for understanding the physiological roles of transmembrane selenoproteins in immunity. Furthermore, as aberrant STING activation has been linked to various pathological conditions, control of STING activity by SELENOK may be a prime therapeutic strategy.
研究领域:
免疫学
·
病毒学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cell and Bioscience
·
2023
·Vol. 13
·期 1
·1-10
·
IF 7.5
Yu Yu,Wang Miao,Li Xiao-Wei,Mao Jie,Zhu Ying-Jie,Wang Na,Yin Le-Hua,Guo Zeng-Lin,Cai Hong,Li Tao,Liang Ting-Ting,Cui Jiuwei,Zhou Tao
Background Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is critical for cytosolic DNA-sensing and the subsequent immune responses. The inappropriate activation of this pathway leads to DNA-induced autoimmune response. Understanding the precise regulation of cGAS-STING pathway is important for developing therapeutics to treat several autoimmune diseases caused by self-DNA.Results We report that Meloxicam (MXC) inhibits intracellular DNA-, but not RNA-induced immune responses. We find that MXC inhibits the phosphorylation of STING by examining in different cells with various DNA stimulations. We further find that MXC significantly dampens the expression levels of interferon-stimulated genes (ISGs) by using DNA 3’ repair exonuclease 1 (TREX1)-deficient cell, an experimental model for self-DNA-induced autoimmune disease. Importantly, we demonstrate that MXC could promote the survival in Trex1–/– mouse model for Aicardi-Goutières syndrome (AGS).Conclusion sOur study identified a non-steroidal anti-inflammatory drug, MXC, that exhibits potential effect in treating the autoimmunity caused by self-DNA.
研究领域:
免疫学
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药理学
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自身免疫疾病
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产品关联
DOI
PubMed
高影响因子
Environment & Health
·
2026
·
IF 6.3
Shiyin Zhong,Qiongli Zhou,Jirui Yang,Zhimin Zhang,Xueting Chai,Jinghao Luo,Xin Zhang,Jingjing Liu,Yangzong Yixi,Lei Shi,Xuhong Chang,Hui Wang
Manganese (Mn) is an essential trace element, but increasing industrial and agricultural use has led to elevated levels of environmental Mn levels. Chronic overexposure to Mn can cause a Parkinson’s-like neurodegenerative disorder; however, the underlying mechanisms remain incompletely understood. This study combined in vitro and in vivo models to investigate the role of the cGAS–STING/NLRP3 axis in regulating the p38 MAPK/NF–κB pathway in the process of Mn-induced Tau aggregation leading to neurotoxicity. Our results demonstrated that MnCl2 exposure significantly activated both the cGAS–STING/NLRP3 signaling axis and the p38 MAPK/NF–κB pathway, accompanied by increased Tau expression. Genetic ablation of cGAS, STING, or NLRP3 attenuated Mn-induced Tau upregulation, indicating that the cGAS–STING/NLRP3 signaling axis mediates Tau expression. RNA-seq analysis further revealed that the decreased Tau expression in knockout cells is associated with the MAPK/NF–κB signaling pathway. Pharmacological inhibition of p38 MAPK or NF–κB markedly downregulated cGAS–STING signaling, inflammatory cytokine release, and phosphorylated Tau (p-Tau) levels. Moreover, we observed colocalization and interaction among p-p38, p-p65, and p-Tau. Overall, these findings reveal that Mn activates the cGAS–STING/NLRP3 signaling axis regulated by the p38 MAPK/NF–κB pathway, driving pathological Tau aggregation.
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高影响因子
iScience
·
2024
·
IF 4.6
Quguang Li,Yifan Yan,Chunjie Wang,Ziliang Dong,Yu Hao,Minming Chen,Zhuang Liu,Liangzhu Feng
Autologous cancer vaccines represent a promising therapeutic approach against tumor relapse. Herein, a concise biomineralization strategy was developed to prepare an immunostimulatory autologous cancer vaccine through protein antigen-mediated growth of flower-like manganese phosphate (MnP) nanoparticles. In addition to inheriting the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING)-activating capacity of Mn 2+ , the resulting ovalbumin (OVA)-loaded MnP (OVA@MnP) nanoparticles with superior stability and pH-responsiveness enabled efficient priming of antigen-specific CD8 + T cell expansion through promoting the endo/lysosome escape and subsequent antigen cross-presentation of OVA. Resultantly, OVA@MnP vaccines upon subcutaneous vaccination elicited both prophylactic and therapeutic effects against OVA-expressing B16-F10 melanoma. Furthermore, the biomineralized autologous cancer vaccines prepared from the whole tumor cell lysates of the dissected tumors suppressed the growth of residual tumors, particularly in combination with anti-PD-1 immunotherapy. This study highlights a simple biomineralization approach for the controllable synthesis of cGAS-STING-activating autologous cancer vaccines to suppress postsurgical tumor relapse.
研究领域:
癌症免疫疗法
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纳米技术
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免疫学
·
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）