JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-20
·
IF 10.6
Zhang Xiaodian,Tian Hailong,Chen Yang,Liang Baichuan,Nice Edouard C.,Huang Canhua,Xie Na,Zheng Shaojiang
Immunotherapy has shown marked progress in promoting systemic anti-colorectal cancer (CRC) clinical effects. For further effectively sensitizing CRC to immunotherapy, we have engineered a pH-sensitive zeolitic imidazolate framework-8 (CS/NPs), capable of efficient cGAS-STING pathway activation and immune checkpoint blockade, by encapsulating the chemotherapeutic mitoxantrone (MTX) and immunomodulator thymus pentapeptide (TP5) and tailoring with tumor-targeting chondroitin sulfate (CS). In this nanoframework, CS endows CS/NPs with specific tumor-targeting activity and reduced systemic toxicity. Of note, the coordinated Zn2+ disrupts glycolytic processes and downregulates the expression of glucose transporter type 1 (GLUT1), thus depriving the cancer cells of their energy. Zn2+ further initiates the adenosine 5’-monophosphate activated protein kinase (AMPK) pathway, which leads to PD-L1 protein degradation and sensitizes CRC cells to immunotherapy. Moreover, the damaged double-stranded DNA during MTX treatment activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which works together with TP5 induced the proliferation and differentiation of T lymphocytes and dendritic cells to further enhance the anti-CRC immune response. Therefore, CS/NPs efficiently sensitize cells to chemotherapy and stimulate systemic antitumor immune responses both in vitro and in vivo, representing a promising strategy to increase the feasibility of CRC immunotherapy.Graphical Abstract
研究领域:
纳米技术
·
癌症免疫治疗
·
分子生物学
·
药学
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DOI
PubMed
高影响因子
MOLECULAR CELL
·
2023
·
IF 16
Sheng Liu,Bo Yang,Yingxiang Hou,Kaige Cui,Xiaozhu Yang,Xiaoxiong Li,Lianwan Chen,Shichao Liu,Zhichao Zhang,Yuanyuan Jia,Yufeng Xie,Ying Xue,Xiaomei Li,Bingxue Yan,Changxin Wu,Wen Deng,Jianxun Qi,Defen Lu,George F. Gao,Peiyi Wang,Guijun Shang
Summary 2′,3′-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the mechanism of STING activation. However, little is known about STING inhibition. Here, we found that apo-STING exhibits a bilayer with head-to-head as well as side-by-side packing, mediated by its ligand-binding domain (LBD). This type of assembly holds two endoplasmic reticulum (ER) membranes together not only to prevent STING ER exit but also to eliminate the recruitment of TBK1, representing the autoinhibited state of STING. Additionally, we obtained the filament structure of the STING/2′,3′-cGAMP complex, which adopts a bent monolayer assembly mediated by LBD and transmembrane domain (TMD). The active, curved STING polymer could deform ER membrane to support its ER exit and anterograde transportation. Our data together provide a panoramic vision regarding STING autoinhibition and activation, which adds substantially to current understanding of the cGAS-STING pathway.
研究领域:
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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PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2023
·
IF 4.6
Chunru Wang,Yingjie Xiang,Wenjie Ma,Chuanlong Guo,Xiaochen Wu
Ulcerative colitis is a chronic inflammatory bowel disease with a high recurrence rate. Natural phytochemical compounds are increasingly being considered as preventative and supportive treatments for this condition. However, the poor water solubility and stability of many of these compounds limit their effectiveness in vivo. To address this issue, fisetin (FT), a natural phytochemical with poor solubility, was stabilized using silk sericin (SS) to create a composite (SS/FT). The therapeutic potential of the SS/FT on ulcerative colitis was extensively investigated, and the results showed that it effectively alleviated the body weight loss and colon length shortening induced by dextran sulfate sodium. Notably, SS/FT downregulated the immune response, decreased colonic histopathological lesions, and reduced the cGAS/STING signal activation. This suggests that SS/FT may offer a promising therapy for treating ulcerative colitis. This article is protected by copyright. All rights reserved
研究领域:
药理学
·
炎症性肠病
·
天然产物化学
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PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Xuan Zhang,Yuhao Shi,Songxiang Xie,Zineng Yi,Zijun Jiang,Yiduo Wang,Zhengbao Zha
Conventional adjuvants such as aluminum salts rarely drive robust Th1 immunity, which limits cancer vaccine efficacy. A double-stranded DNA-loaded manganese phosphate nanoadjuvant was generated by dsDNA-templated biomimetic mineralization. The resulting DNA@MnP exhibited favorable physiological stability and pH-responsive release properties: at pH 5.5, the cumulative release rates of Mn2+ and DNA reached 72% and 78%, respectively, within 12 h. Following cytosolic delivery, released Mn2+ from DNA@MnP could augment the cGAS recognition of dsDNA. The cooperative action of Mn2+ and dsDNA produced cascade amplification that potently activated the cGAS-STING pathway in dendritic cells. In vitro experiments demonstrated that DNA@MnP significantly promoted the maturation of BMDCs (with a maturation rate 2.10-fold elevation compared with the control group) and induced RAW264.7 macrophages to polarize toward the M1 phenotype (with an M1/M2 ratio 8.31-fold elevation compared with the control group). Animal experiments demonstrated that DNA@MnP not only significantly enhanced antigen-specific humoral immunity, achieving a 16-fold increase in IgG titers, and elicited a balanced Th1/Th2 response but also effectively activated both innate and adaptive antitumor immunity. Furthermore, this platform was extended to develop a personalized tumor vaccine by encapsulating tumor lysates (TLs) into TLs-loaded manganese phosphate nanovaccines (TLs@MnP). When coadministered with an anti-TIGIT antibody, it potently suppressed tumor growth, recurrence, and metastasis: in the postoperative recurrence model, 42.9% of mice in the TLs@MnP multidose combined with aTIGIT group achieved long-term tumor-free survival. Therefore, this study presented a manganese phosphate-based biomineralization strategy for the concise preparation of autologous tumor vaccines, opening a promising avenue for personalized immunotherapy and clinical translation.
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PubMed
高影响因子
Toxics
·
2026
·Vol. 14
·期 6
·461
·
IF 4.9
Xiangyu Yu,Jiawen Ren,Ying Kang,Shizhi Wang,Jianrui Dou,Yongquan Yu
Glyphosate, the most widely used herbicide worldwide, is now ubiquitous in the environment, posing a growing threat to human health. While accumulating evidence has linked glyphosate exposure to liver injury, the underlying mechanisms remain unclear. In this study, based on data from NHANES 2013–2018, we identified significant associations between glyphosate exposure and abnormal liver function parameters in the general US population. A glyphosate-exposed mouse model was further established, and the results showed that hepatic accumulation of glyphosate induced direct histopathological damage and increased serum AST, ALT, and ALP levels in mice. Combined network toxicology and gene set analyses revealed that glyphosate activated liver macrophages, upregulating genes related to lipid metabolism, inflammation, and pyroptosis. The activation of the pyroptosis pathway was further confirmed by Western blot analysis of NLRP3 inflammasome-associated proteins. Mechanistically, glyphosate disrupted mitochondrial membranes and compromised mitochondrial function, leading to the release of mtDNA, which subsequently activated the cGAS-STING pathway in mouse livers and RAW264.7 macrophages. Moreover, glyphosate-induced NLRP3 activation in RAW264.7 cells was attenuated by the cGAS inhibitor. These findings provide a novel mechanistic insight into glyphosate-induced hepatotoxicity and reinforce the growing concern over its association with liver injury in humans.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Yanming Xia,Bo Shi,Keke Wang,Lixin Hu,Qiran Wang,Shuxian Xu,Xiaohu Wang,Pengcheng Xu,Yuanbin She,Haitang Xie,Suxin Li,Lifang Yin
The cGAS-STING axis is a promising therapeutic target against cancer. However, most activators require STING signaling in the host, especially within antigen-presenting cells, which are rare in a cold tumor microenvironment. The cGAS-STING cascade is also present within cancer cells but with suppressed activity. Such a paradoxical situation may account for the clinical failures. Herein, we develop a trinity STING-activating nanoparticle (CMTP) coordinated with cGAMP, Mn 3+ , and porphyrin to awaken autologous STING signaling in cancer cells. CMTP disintegrates into Mn 2+ and TCPP upon elevated glutathione in cancer cells, where TCPP triggers mitochondrial DNA leakage, enhancing cGAS enzymatic activity in coordination with Mn 2+ , while concurrent cGAMP release from framework synergizes to amply STING activity. Consequently, CMTP exploits cancer cells as reservoirs for cGAS-STING signaling to promote DC maturation and T cell priming. A single administration of CMTP demonstrates robust efficacy in both hot MC38 and cold 4 T1 murine tumors. Genetic knockout studies confirm that STING in cancer cells, rather than in the host, is critical for antitumor performance. The feasibility of immune modulation is further validated in resected human patient tissues. This work presents a potent STING-activating nanomedicine based on coordination chemistry and underscores the potential of harnessing cancer cells' autologous cGAS-STING machinery in immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
药剂学
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Yonglong Jin,Nina Dong,Shosei Shimizu,Yinuo Li,Yuan Yao,Hong Qiao,Xiguang Liu,Shuai Liu,Chuanlong Guo,Lijie Wang
The incidence rate and mortality rate of breast cancer remain high, and there is an urgent need for safe and effective drugs. The excellent biological activity of hesperidin (HE) is a potential drug for the treatment of breast cancer. In this study, silk fibroin peptides (SFP) were used as delivery carriers and HE loaded SFP nanofibers (SFP/HE NFs) was prepared. The in vitro results showed that SFP/HE NFs significantly inhibited the proliferation and migration of breast cancer cell MDA-MB-231 compared with free HE. The mechanism results demonstrated that SFP/HE NFs induced apoptosis and DNA double stranded damage (DSBs) and further activated the cyclic monophosphate guanosine adenosine monophosphate synthase- stimulator of interferon gene (cGAS-STING) pathway. The in vivo studies showed that SFP/HE NFs treatment significantly inhibited the growth of breast cancer, with an inhibition rate of 65.9 % (100 mg/kg). In vivo mechanism studies also demonstrated that the anti-tumor activity of SFP/HE NFs was related to the activation of the cGAS-STING pathway. Interestingly, we found that the combination of SFP/HE NFs and cisplatin not only enhanced the anti-tumor activity of cisplatin, but also alleviated cisplatin induced nephrotoxicity. In conclusion, our results demonstrate the benefits of activating the cGAS-STING pathway in the treatment of breast cancer, which is expected to provide potential candidates for combined treatment of breast cancer.
研究领域:
药理学
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肿瘤学
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生物材料科学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Yan Zhang,Chunhua Yin,Xiaoling Yuan,Shu Xu
Background Rheumatoid arthritis (RA) is a complex disorder characterized by joint synovitis, cartilage degradation, and bone destruction. Its etiology remains largely unexplored. This study aimed to investigate the potential roles of lactate and the underlying mechanisms contributing to RA pathogenesis. Methods A total of 10 adult patients with active RA and 10 matched patients with noninflammatory joint diseases, such as injuries or traumatic fractures, admitted to our hospital were enrolled in this research. Synovial tissues were collected from the participants. A collagen-induced arthritis (CIA) mouse model was established, and tissues were collected for isolation of synovial primary macrophages. The pathological characteristics of tissue samples were observed using H&E and safranin O staining. The THP-1 cells and mouse synovial primary macrophages were cultured and transfected. The level of dsDNA was evaluated using immunofluorescent staining and Qubit method. The production of proinflammatory cytokines was measured by ELISA kits. The activation of the cGAS-STING signaling pathway was confirmed by immunofluorescent staining, western blot and co-IP methods. Results The level of dsDNA in the synovial primary macrophage of RA patients and CIA mice was increased, accompanied by an increase in lactate levels. Lactate promoted the production of inflammatory cytokines in THP-1 cells and synovial primary macrophages from mice. Expression of cGAS was also elevated in synovial primary macrophages of RA patients and CIA mice. Lactate activated the cGAS-STING signaling pathway, while knockdown of cGAS inhibited the cytokine production. Knockdown of STING ameliorated the tissue damage in the CIA mouse model. Lactate exerted its proinflammatory effects through lactylation of cGAS, preventing its degradation and thereby activating the cGAS-STING signaling pathway to promote inflammation and exacerbate RA. Conclusion Lactate might activate the cGAS-STING signaling pathway, thereby accelerating RA progression in macrophages. This study identified a potential therapeutic target for the treatment of RA in the future.
研究领域:
免疫学
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风湿病学
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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
TOXICOLOGY LETTERS
·
2026
·
IF 2.9
Liwei Yang,Zhili Ge,Xuehan Ding,Jingjing Shi,Jiaxin Zhang,Tianyou Wang,Huibin Jiang,Xinyu Zhang,Liting Zhou
Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid metabolic disorders. Rats and BRL-3A cells are used as models to determine the liver toxicity of TBP. Aspirin was used to alleviate the inflammation induced by TBP. RU.521 and H151 were employed to inhibit the activation of cGAS-STING. HE staining was applied to observe liver injury. The mitochondrial structure was observed with transmission electron microscopy. The quantification of lipid levels was achieved through colorimetry. The concentrations of inflammatory factors were assessed by ELISA. The expression levels of genes involved in lipid metabolism and cGAS-STING signaling pathway were detected by Q-PCR and western blot. TBP induced hepatocyte swelling and disorganized cord structures of rat livers. Following exposure to TBP, there is an elevation in the concentrations of triglycerides (TG) and total cholesterol (T-CHO), and the mRNA and protein expression levels of FASN, SREBP2, and PPARγ also showed a significant increase( P < 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment( P < 0.05). In BRL-3A cells, inhibiting cGAS-STING signaling pathway decreased the IL-6 concentrations and reversed the lipid accumulation caused by TBP( P < 0.05). Taken together, our results suggest TBP induced histopathological damage in rat livers, including hepatocyte swelling and disorganized cord structures. It also caused alterations in mitochondrial structure. Moreover, TBP can mediate inflammatory responses via the cGAS-STING, which in turn leads to hepatic lipid accumulation.
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Li Muzi,Zhao Ruyang,Wang Qiqian,Chen Jing,Ma Xiaoyang,Wang Haoran,Li Jinlong
Di(2-ethylhexyl) phthalate (DEHP)
is a widespread environmental
pollutant with neurotoxicity, while lycopene (LYC) is a neuroprotective
dietary carotenoid. This study investigated whether LYC alleviates
DEHP-induced brain injury by regulating microglial activation and
cGAS-STING signaling. ICR mice were treated with LYC (5 mg/kg) and/or
DEHP (500 mg/kg) for 28 days, with results validated in BV2 cells.
In vivo, DEHP exposure impaired spatial learning and memory, triggered
neuronal degeneration, microglial activation and mitochondrial dysfunction,
increased 2 ′ 3 ′ -cGAMP production, and activated cGAS-STING
signaling. LYC supplementation markedly reversed these changes. Network
toxicology, molecular docking, and molecular dynamics suggested cGAS
as a potential LYC target. In vitro, MEHP-induced M1 polarization
was attenuated by LYC, and cGAS silencing verified the pathway’s
critical role in LYC’s protection. These findings indicate
that LYC alleviates DEHP-induced neural damage by maintaining mitochondrial
homeostasis and inhibiting cGAS-STING-mediated microglial activation,
providing a potential nutritional strategy for preventing brain damage
caused by environmental pollutants.
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高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Xiawei Zhou,Xiuhua Pan,Ziqi Shen,Ruixin Kang,Yueru Pang,Lin Luo,Feiyang Liu,Siyuan Yu,Jun Zhang,Qi Shen
Breast cancer remains a leading cause of cancer-related mortality in women, with intratumoral bacteria playing a significant role in immunosuppression. However, targeted therapeutic strategies to address this microbial influence remain underexplored. In this study, we developed a novel nanodrug bacteria biohybrid system, LGG-PDA@Cu-CPT, which integrated Lactobacillus rhamnosus GG (LGG) probiotics, polydopamine (PDA), and copper-irinotecan (Cu-CPT) composites to potentiate cancer immunotherapy by simultaneously eliminating immunosuppressive intratumoral bacteria and activating the cGAS–STING pathway, thereby suppressing tumor progression. Photothermal therapy (PTT) mediated by PDA enhanced intratumoral bacterial eradication by disrupting bacterial membranes and promoting intracellular Cu 2+ uptake. Cu 2+ ions further induced reactive oxygen species (ROS) generation through Fenton-like reactions, effectively killing intratumoral Fusobacterium nucleatum (Fn) bacteria and thereby relieving the bacterium-induced immunosuppressive tumor microenvironment. Concurrently, the acidic tumor microenvironment and PTT-induced heating facilitated the release of CPT, which, together with LGG , activated the cGAS-STING pathway. This activation triggered robust type I interferon production, dendritic cell (DC) maturation, and cytotoxic T lymphocyte (CTL) infiltration, leading to effective immune-mediated tumor cell clearance. Additionally, Fn bacterial remnants acted as immunostimulatory agents, further amplifying immune responses. This synergistic strategy of bacterial elimination and cGAS-STING activation significantly enhanced antitumor immune responses and inhibited tumor progression, providing a promising therapeutic approach for breast cancer treatment.
研究领域:
癌症生物学
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免疫学
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纳米医学
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微生物学
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药理学
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DOI
PubMed
高影响因子
Small
·
2025
·
IF 12.1
Jingjing Zhang,Fan Xie,Yunyang Zhang,Siying Chen,Wenjun Shi,Xinyan Yang,Yunjiu Ren,Yao Li,Mayakrishnan Arumugam,Xiangdong Kong,Ruibo Zhao
Dissolvable microneedle-based transdermal superficial technique demonstrates promised integrative potential for triple-negative breast cancer (TNBC) therapy, yet their insufficient mechanical strength restricts to puncture, attributed to the high-density tumor stroma and elasticity of TNBC, limiting long-distance therapeutics penetration and profound treatment in situ, posing a significant barrier to achieving effective therapy for TNBC management. Inspired by biomineralization, herein, a novel strategy is presented for a robust microneedle involving manganese phosphate biomimetic mineralization, which is characterized by a homogeneous inorganic–organic intercross modification, achieving high mechanical strength and solubility. Furthermore, the chemotherapy drug, doxorubicin (DOX), can be facilely integrated into this biomimetic process, facilitating chemoimmunological microneedles (MD-MN). Subsequently, the MD-MN provides high robustness for tumor injection followed by releasing manganese and DOX within the tumor, and the manganese can reduce tumor stroma and enhance deep DOX infiltration, exerting significant cancer cell apoptosis. Furthermore, manganese elements can reverse the immunosuppressive microenvironment by activating cGAS-STING, which taken together, constructs a boosted cascade chemoimmunological therapy for TNBC. These achievements present a successful integrative strategy for circulated cascade chemoimmunological treatment for TNBC, indicating a great potential of biomineralization-based cancer medicine, further demonstrating insights into biomimetic physiological reactions for material construction and translational medicine.
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高影响因子
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