Biomaterials Research
·
2023
·Vol. 27
·期 1
·1-16
·
IF 11.3
He Qingbin,Zheng Runxiao,Ma Junchi,Zhao Luyang,Shi Yafang,Qiu Jianfeng
Background The activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has attracted great attention for its ability to up-regulate innate immune response and thus enhance cancer immunotherapy. However, many STING agonists limit the further advancement of immunotherapy due to weak tumor responsiveness or low activation efficiency. The responsive and effective activation of cGAS-STING signaling in tumors is a highly challenging process. Methods In this study, a manganese-based nanoplatform (MPCZ NPs) was constructed that could responsively and efficiently generate more manganese ions (Mn 2+ ) and reactive oxygen species (ROS) to activate cGAS-STING signaling pathway. Briefly, manganese dioxide (MnO 2 ) was loaded with zinc protoporphyrin IX (ZPP) molecule and coated by polydopamine (PDA) embedded with NH 4 HCO 3 to obtain MPCZ NPs. Additionally, MPCZ NPs were evaluated in vitro and in vivo for their antitumor effects by methyl thiazolyl tetrazolium (MTT) assay and TUNEL assays, respectively. Results In this system, tumor responsiveness was achieved by exogenous (laser irradiation) and endogenous (high levels GSH) stimulation, which triggered the collapse or degradation of PDA and MnO 2 . Moreover, the release of Mn 2+ augmented the cGAS-STING signaling pathway and enhanced the conversion of hydrogen peroxide (H 2 O 2 ) to hydroxyl radical (·OH) under NIR laser irradiation. Furthermore, the release of ZPP and the elimination of GSH by MPCZ NPs inhibited HO-1 activity and prevented ROS consumption, respectively. Conclusions This adopted open source and reduce expenditure strategy to effectively generate more ROS and Mn 2+ to responsively activate cGAS-STING signaling pathway, providing a new strategy for improving immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Ru-Yang Zhao,Mu-Zi Li,Qi-Qian Wang,Fu-Wei Jiang,Yi Zhao,Jin-Long Li
Butachlor (BTR), a globally prevalent amide herbicide, poses significant environmental health risks due to its bioaccumulation potential and documented chronic toxicity in mammalian systems. Given the spleen's pivotal role in orchestrating systemic immune homeostasis, this study investigated BTR-induced immunopathological mechanisms in ICR mice following 28-day subacute exposure (10 mg/kg). Histopathological examination revealed significant disorganization of the splenic marginal zone architecture, concomitant with ultrastructural mitochondrial abnormalities and a reduction in mitochondrial membrane potential (ΔΨm). Mitochondrial permeability transition pore opening triggered cytoplasmic translocation of mitochondrial DNA (mtDNA), activating the stimulator of interferon genes (STING) pathway—a master regulator of innate immunity. STING activation initiated bifurcated downstream signaling, evidenced by TBK1 phosphorylation and subsequent IRF3 / NF-κB nuclear translocation. This dual signaling cascade simultaneously executed immunogenic cell death via Gasdermin D-dependent pyroptosis (cleaved GSDMD-NT) and drove macrophage polarization (IFN-α / β, IL-1β, TNF-α). Crucially, pharmacological STING inhibition with C-176 attenuated both pyroptosis (GSDMD cleavage reduced) and inflammatory cytokine surge. Our findings not only pioneer the identification of the mtDNA-STING axis as the central mechanism underlying BTR-induced splenic immunotoxicity but also validate STING inactivation as a targeted strategy to mitigate herbicide-associated immune dysfunction. This work provides critical insights for environmental toxicant risk assessment and immunomodulatory.
研究领域:
环境毒理学
·
免疫学
·
分子生物学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
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
·
免疫学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Xintao Gao,Yulan Yin,Shuai Liu,Kehong Dong,Jing Wang,Chuanlong Guo
Fucoidan (FU) is a natural polymer from marine organisms, which has been widely studied and applied in drug delivery. In this study, FU nanoparticles loaded with proanthocyanidins (PCs) (FU/PCs NPs) were prepared and their effect and mechanism in protecting cisplatin-induced acute kidney injury (AKI) were studied. The in vitro studies confirmed that FU/PCs NPs increased the antioxidant activity of free PCs and protected the death of human kidney proximal tubule (HK-2) cells induced by cisplatin. Further mechanism studies showed that FU/PCs NPs protected the mitochondrial damage induced by cisplatin, activated mitophagy, inhibited the release of mitochondrial DNA (mtDNA), and inhibited the cGAS/STING signal pathway. The in vivo results also indicated that FU/PCs NPs protected cisplatin-induced AKI, including inhibiting the increase of blood urea nitrogen (BUN) and serum creatinine (SCr) levels induced by cisplatin. The mechanism studies confirmed that cisplatin induced an increase in the expression of mitophagy-related protein Pink/Pakrin, mitochondrial mtDNA release and cGAS/STING expression in mice kidney tissues. Pre-administration of FU/PCs NPs further activated mitophagy, as well as inhibiting mtDNA release and cGAS/STING expression. In conclusion, our research proved the role of mitophagy-mtDNA-cGAS/STING signal was involved in cisplatin-induced AKI.
研究领域:
药理学
·
肾病学
·
分子生物学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2025
·
IF 26.3
Jing Han,Shuhao Zhang,Yanfei Hou,Yi Wang,Zhengyin Zhang,Jiaming Yang,Yifang Xu,Zexu Peng,Hang Yin,Kehong Chen,Xiangyu Liu,Conggang Zhang
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is critical in innate immunity. Recent research has highlighted the importance of phosphatidylinositol 4-phosphate (PI4P) signaling within the Golgi apparatus for STING activation. However, the exact molecular mechanisms by which PI4P regulates STING have remained unclear. Here, we report the activation mechanism of STING triggered by PI4P and a chemical STING agonist, GNE-6468. Utilizing cryoelectron microscopy, we determined that GNE-6468 bound to a distinct pocket within the STING transmembrane (TM) domain, promoting outward movements of the STING TM3 helix without altering the conformation of the ligand-binding domain. Notably, we provided structural insights into STING bound to both PI4P and GNE-6468, and they collectively induced STING oligomerization and STING-mediated immune responses. Functional assays further confirmed that the interactions among STING, PI4P, and GNE-6468 were essential for STING activation. Collectively, these results demonstrate that PI4P and GNE-6468 cooperatively bind STING to activate its signaling, highlighting its therapeutic potential.
研究领域:
免疫学
·
结构生物学
·
细胞信号传导
·
天然免疫
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
IMMUNITY
·
2025
·
IF 26.3
Zhimeng Wang,Yanfei Hou,Peiyuan Liu,Ruinan Wu,Jiaming Yang,Shilong Fan,Zexu Peng,Xiaoxu Han,Bin Su,Conggang Zhang
The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway mediates antiviral innate immunity upon sensing cytosolic DNA. Here, we examined the impact of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a paralog of the LXR lipid metabolism-induced cGAMP-degrading enzyme SMPDL3A, on viral infection. We found that SMPDL3B was induced and stabilized by both viral infection and membrane-disturbing agents, suggesting a role in sensing membrane stress as an early signal of cellular danger. Deletion of SMPDL3B impaired DNA virus infection. Upon induction, SMPDL3B suppressed cGAS-STING signaling and downstream transcriptional pathways, including the interferon response. Mechanistically, SMPDL3B functioned as a cGAMP hydrolase; cGAMP-induced SMPDL3B dimerization enabled its hydrolase activity and a negative feedback loop that dampened STING signaling. SMPDL3B-deficient cells had elevated cGAMP concentrations, and Smpdl3b −/− mice exhibited enhanced cGAMP accumulation, heightened immune activation, and reduced viral loads upon herpes simplex virus type 1 (HSV-1) infection. Thus, SMPDL3B links membrane stress to modulation of cGAS-STING signaling through cGAMP degradation, with potential implications in the contexts of inflammation or autoimmunity.
研究领域:
免疫学
·
病毒学
·
细胞生物学
·
先天免疫
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-23
·
IF 12.6
Gong Zhaoyang,Chen Zhenhao,Li Dachuan,Lu Xiao,Wu Jianwei,Sun Hanqiu,Wang Ximeng,Liu Siyang,Xia Xinlei,Lu Feizhou,Jiang Jianyuan,Sun Chi,Wang Hongli,Zeng Feng,Ma Xiaosheng
Background Spinal cord injury (SCI) treatment remains a formidable challenge, as current therapeutic approaches provide only marginal relief and fail to reverse the underlying tissue damage. This study aims to develop a novel composite material combining enzymatic nanoparticles and nerve growth factor (NGF) to modulate the immune microenvironment and enhance SCI repair.Methods CeMn nanoparticles (NP) and CeMn NP-polyethylene glycol (PEG) nanozymes were synthesized via sol–gel reaction and DSPE-mPEG modification. Transmission Electron Microscopy, Selected-Area Electron Diffraction, X-ray Diffraction and X-ray Photoelectron Spectroscopy confirmed their crystalline structure, mixed-valence states, and redox properties. Size uniformity, biocompatibility, and catalytic activity were assessed via hydrodynamic diameter, zeta potential, and elemental analysis. The Lightgel/NGF/CeMn NP-PEG composite was synthesized and characterized via electron microscopy, compression testing, rheological analysis, NGF release kinetics, and 30-day degradation studies. Both in vitro and in vivo experiments were conducted to evaluate the therapeutic effects of the composite on SCI.Results The Lightgel/NGF/CeMn NP-PEG composite was successfully synthesized, exhibiting favorable physical properties. At a CeMn NP-PEG concentration of 4 µg/mL, the composite maintained cell viability and demonstrated enhanced biological activity. It also showed superior mechanical properties and an effective NGF release profile. Notably, the composite significantly upregulated the expression of nerve growth-associated proteins, reduced inflammatory cytokines, scavenged reactive oxygen species (ROS), and promoted M2 macrophage polarization by inhibiting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. In a rat SCI model, it facilitated functional recovery and attenuated inflammation.Conclusion The Lightgel/NGF/CeMn NP-PEG composite shows significant therapeutic promise for SCI, effectively eliminating ROS, promoting M2 macrophage polarization, reducing pro-inflammatory cytokines, and supporting neuronal regeneration. These effects substantially enhance motor function in SCI rats, positioning it as a promising candidate for future clinical applications.Graphical
研究领域:
生物医学工程
·
纳米技术
·
神经科学
·
免疫学
·
组织工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Shufen Zhang,Yingping Zeng,Kai Wang,Guangtao Song,Yiru Yu,Tingting Meng,Hong Yuan,Fuqiang Hu
Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway is an essential DNA-sensing pathway to regulate the innate and adaptive immune response, which plays an important role in tumor immunotherapy. Although the STING agonists can be used, they are limited by their inability to target immune cells and systemic immunotoxicity, calling for novel strategies to accurately and effectively activate the cGAS-STING signaling pathway. Herein, mannose-modified stearic acid-grafted chitosan (M-CS-SA) micelles with the ability to activate the cGAS-STING signaling pathway and absorb tumor antigens were constructed. The chitosan-based nano-micelles showed valid dendritic cell (DCs) targeting and could escape from lysosomes leading to the activation of the cGAS-STING signaling pathway and the maturation of DCs. In addition, a combinatorial therapy was presented based on the programmed administration of oxaliplatin and M-CS-SA. M-CS-SA adsorbed tumor antigens released by chemotherapy to construct an autologous tumor vaccine and built a comprehensive antitumor immune response. In vivo , the combinatorial therapy achieved a tumor inhibition rate of 76.31 % at the oxaliplatin dose of 5 mg/kg and M-CS-SA dose of 15 mg/kg, and increased the CD3 + CD8 + T cell infiltration. This work demonstrated that M-CS-SA and its co-treatment with oxaliplatin showed great potential in tumor immunotherapy.
研究领域:
药学
·
免疫学
·
纳米技术
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2024
·
IF 18
An Shao,Lulu Jin,Yanni Ge,Ziqiang Ye,Mingyu Xu,Yifan Zhou,Yingyu Li,Linyan Wang,Pinglong Xu,Kai Jin,Zhengwei Mao,Juan Ye
Retinal neovascularization (RNV), a typical pathological manifestation involved in most neovascular diseases, causes retinal detachment, vision loss, and ultimately irreversible blindness. Repeated intravitreal injections of anti-VEGF drugs were developed against RNV, with limitations of incomplete responses and adverse effects. Therefore, a new treatment with a better curative effect and more prolonged dosage is demanding. Here, we induced macrophage polarization to anti-inflammatory M2 phenotype by inhibiting cGAS-STING signaling with an antagonist C176, appreciating the role of cGAS-STING signaling in the retina in pro-inflammatory M1 polarization. C176-loaded and phosphatidylserine-modified dendritic mesoporous silica nanoparticles were constructed and examined by a single intravitreal injection. The biosafe nanoparticles were phagocytosed by retinal macrophages through a phosphatidylserine-mediated “eat me” signal, which persistently release C176 to suppress STING signaling and thereby promote macrophage M2 polarization specifically. A single dosage can effectively alleviate pathological angiogenesis phenotypes in murine oxygen-induced retinopathy models. In conclusion, these C176-loaded nanoparticles with enhanced cell uptake and long-lasting STING inhibition effects might serve as a promising way for treating RNV.
研究领域:
眼科学
·
纳米技术
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Han Yan,Wenting Cheng,Siyuan Qin,Jing Zuo,Lei Li,Jing Zhang,Qinxia Chang,Yonghao Yan,Shiqi Wang,Canhua Huang,Haiyuan Zhang
The blood–brain barrier (BBB) caused limited drug accumulation and programmed death-ligand 1 (PD-L1) compromised immunosuppressive microenvironment are bottlenecks in glioblastoma multiforme (GBM) treatment. Herein, we bioengineered a human heavy chain nanoferritin (HTE NPs) for GBM-specific delivery and efficient immunotherapy. To achieve targeted mitochondrial metabolic regulation, we connected triphenylphosphonium (TPP) with the photosensitive agent IR780 to form T780, which self-assembles with esomeprazole magnesium (EM) and human H-ferritin (HFn) to obtain HTE NPs. HFn endows HTE NPs with BBB penetration and specific site-targeting capabilities, thereby enhancing tumor accumulation and pH-responsive release within GBM cells. T780 subsequently induces mitochondrial damage, activating the AMP-dependent protein kinase (AMPK) pathway and blocking the transmission of T-cell inhibitory signals through the phosphorylation of PD-L1, thereby promoting T-cell activation. Moreover, EM inhibits the release of extracellular vesicles (EVs), reducing the inhibitory effect of PD-L1 on circulating T cells. Furthermore, mitochondrial impairment-induced mitochondrial DNA (mtDNA) leakage activates the cGAS-STING signaling pathway, inducing the maturation of dendritic cells (DCs), recruiting supportive immune cells to clear GBM cells, and improving the immunosuppressive microenvironment. Therefore, HTE NPs not only achieve efficient tumor accumulation but also facilitate the activation immune response, providing a promising strategy for the clinical treatment of GBM.
研究领域:
肿瘤学
·
神经科学
·
纳米技术
·
免疫学
✓ 已验证
DOI
高影响因子
ACS Nano
·
2024
·
IF 15.8
Yuhua Cao,Shuaishuai Ding,Yunping Hu,Lijuan Zeng,Jingrong Zhou,Ling Lin,Xiao Zhang,Qinghua Ma,Ruili Cai,Yu Zhang,Guangjie Duan,Xiu-wu Bian,Gan Tian
cGAS-STING signaling plays a critical role in radiotherapy (RT)-mediated immunomodulation. However, RT alone is insufficient to sustain STING activation in tumors under a safe X-ray dose. Here, we propose a radiosensitization cooperated with cGAS stimulation strategy by engineering a core–shell structured nanosized radiosensitizer-based cGAS-STING agonist, which is constituted with the hafnium oxide (HfO2) core and the manganese oxide (MnO2) shell. HfO2-mediated radiosensitization enhances immunogenic cell death to afford tumor associated antigens and adequate cytosolic dsDNA, while the GSH-degradable MnO2 sustainably releases Mn2+ in tumors to improve the recognition sensitization of cGAS. The synchronization of sustained Mn2+ supply with cumulative cytosolic dsDNA damage synergistically augments the cGAS-STING activation in irradiated tumors, thereby enhancing RT-triggered local and system effects when combined with an immune checkpoint inhibitor. Therefore, the synchronous radiosensitization with sustained STING activation is demonstrated as a potent immunostimulation strategy to optimize cancer radio-immuotherapy.
研究领域:
癌症生物学
·
纳米技术
·
免疫学
·
放射肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Qiang Zhou,Meiyu Chang,Shuhan Guo,Yiming Zhang,Qiufang Qu,Qingnan Zhou,Zhiheng Li,Sanqiao Yao
Silicosis is a life-threatening occupational disease because of inhaling silica dust, leading to chronic inflammation, pyroptosis, and fibrosis. Unfortunately, it is still lacking effective pharmacological intervention currently. Honokiol ( HKL ), a natural extract with biological activity from Magnolia bark, is known for its antioxidant and anti-inflammatory biological effects. The current work aimed to investigate the therapeutic potential of HKL in mitigating silica-induced lung fibrosis and pyroptosis, particularly focusing on the cGAS/STING signaling pathway. The pulmonary pathological results shown in H&E and Masson’s trichrome staining images confirmed the protective effects of HKL on lung tissue structure. In addition, HKL significantly reduced lung inflammation, collagen deposition, and oxidative stress compared to mice in the silicosis group. HKL treatment also alleviated silica-induced pyroptosis by suppressing the activation of the cGAS/STING signaling pathway in lung tissues. Moreover, the in vitro experiments using J774A.1 macrophages demonstrated that HKL reduced pyroptosis and improved cell viability under exposure to silica combined lipopolysaccharide (LPS). These were attributed to HKL downregulating the activation of the cGAS/STING signaling pathway in pyroptotic J774A.1 cells induced by silica combined with LPS. Meanwhile, inhibition of STING signaling induced by DNase I significantly enhanced the protective effects of HKL on the inflammatory and pyroptotic processes induced by silica. Overall, HKL could attenuate silica-induced pyroptosis by modulating the cGAS/STING signaling pathway against pulmonary fibrosis. The current study offers a promising approach for treating silicosis and related inflammatory responses.
研究领域:
药理学
·
肺病学
·
免疫学
·
分子生物学
✓ 已验证
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）