Nature Communications
·
2022
·Vol. 13
·期 1
·1-22
·
IF 17.694
Wang Xuan,Liu Yingqi,Xue Chencheng,Hu Yan,Zhao Yuanyuan,Cai Kaiyong,Li Menghuan,Luo Zhong
cGAS-STING pathway is a key DNA-sensing machinery and emerges as a promising target to overcome the immunoresistance of solid tumors. Here we describe a bovine serum albumin (BSA)/ferritin-based nanoagonist incorporating manganese (II) ions and β-lapachone, which cooperatively activates cGAS-STING signaling in dendritic cells (DCs) to elicit robust adaptive antitumor immunity. Mn 2+ -anchored mannose-modified BSAs and β-lapachone-loaded ferritins are crosslinked to afford bioresponsive protein nanoassemblies, which dissociate into monodispersive protein units in acidic perivascular tumor microenvironment (TME), thus enabling enhanced tumor penetration and spatiotemporally controlled Mn 2+ and β-lapachone delivery to DCs and tumor cells, respectively. β-lapachone causes immunogenic tumor cell apoptosis and releases abundant dsDNA into TME, while Mn 2+ enhances the sensitivity of cGAS to dsDNA and augments STING signaling to trigger downstream immunostimulatory signals. The cGAS-STING nanoagonist enhances the tumor-specific T cell-mediated immune response against poorly immunogenic solid tumors in vivo, offering a robust approach for immunotherapy in the clinics.
研究领域:
免疫学
·
肿瘤学
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纳米技术
·
药学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2023
·
IF 8.8
Zhiqiang Zhang,Li Wang,Xia Ma,Hui Wang
A series of biodegradable nanoparticle-based drug delivery systems have been designed utilizing poly(β-amino ester)-guanidine-phenylboronic acid (PBAE-G) polymers. In this study, a novel Lentinan-Functionalized PBAE-G-nanodiamond system was developed to carry ovalbumin (LNT-PBAE-G-ND@OVA). The impact of this drug delivery system on the activation and maturation of macrophages was then assessed. Furthermore, LNT-PBAE-G-ND@OVA induced potent antibody response and showed no obvious toxicity in vitro and in vivo . Moreover, treatment with LNT-PBAE-G-ND@OVA was sufficient to alter the expression of genes associated with the cGAS-STING pathway, and the LNT-PBAE-G-ND@OVA induced upregulation of costimulatory molecules. LNT-PBAE-G-ND@OVA treatment was sufficient to induce macrophage activation through a complex mechanism in which cGAS-STING signaling plays an integral role.
研究领域:
纳米技术
·
免疫学
·
药学
·
分子生物学
✓ 已验证
DOI
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Kun Shang,Dongsheng Tang,Minhui Cui,Hongyi Hou,Bing Xiao,Jinjian Liu,Ruoshi Zhang,Rui Kuai,Jianfeng Liu,Haihua Xiao,Fan Huang,Jianliu Wang
Cisplatin is a first-line, broad-spectrum anti-tumor drug used to treat various types of cancer. However, immune-suppressive tumor microenvironments (TME) are often induced by cisplatin. Here, a first synthetic high-density lipoprotein (sHDL) nanodisc, referred as sHDL@Pt, is engineered to load a Pt(IV) prodrug (C2-Pt(IV)-C12), inducing a 2.2-fold increase in dsDNA release compared to cisplatin. This further activates the innate immune system through the cGAS-STING pathway. Using near-infrared II fluorescence imaging and single photon emission computed tomography imaging technology, it is found that sHDL@Pt can be effectively accumulated in tumor sites. The sHDL@Pt can induce severe DNA damage, which subsequently results in a more pronounced activation of the cGAS-STING pathway, further promoting dendritic cell maturation and T cell proliferation, triggering strong cytotoxic T lymphocyte responses, and inhibiting tumor growth. This work introduces a novel approach for delivering Pt(IV) prodrug that effectively initiates and activates innate immunity through the activation of the cGAS-STING pathway.
研究领域:
纳米医学
·
肿瘤学
·
免疫治疗
·
药理学
·
生物工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Yixing Huang,Xiao Li,Shengfeng Xu,Dan Zu,Haidong Liu,Hanyi He,Qimei Bao,Yanhua He,Chen Liang,Yin Shi,Xiangdong Cheng,Yaoshu Teng,Zu Ye
Nanoplastics (NPs), which are characterized by plastic particles smaller than one micrometer, have emerged as pervasive environmental pollutants, raising concerns about their potential toxicity to living organisms. Numerous investigations have highlighted the tendency of NPs to accumulate in organs, resulting in toxic effects. Despite polyvinyl chloride (PVC) being one of the most prevalent NPs, its impact on the esophagus and the associated underlying mechanisms remain largely unknown. In this study, we investigated the impact of PVC NPs on the esophagus and found that PVC NPs exposure induces oxidative stress and elicits DNA damage responses. Further analysis revealed that PVC NPs inhibit the homology-directed repair (HDR) pathway by suppressing the expression of breast cancer susceptibility gene 2 ( BRCA2 ) and growth factor receptor-bound protein 2 ( GRB2 ), resulting in genomic instability. Additionally, the release of free DNA activates cGAS-STING and the downstream NF-κB signaling, elevating inflammatory factors and chemokines, which further leads to cellular senescence. In vivo experiments corroborated these findings, showing that PVC NPs induced oxidative stress, inflammation, and cellular senescence, subsequently impacting mouse behavior. This study contributes novel insights into the health risks associated with PVC NPs exposure and identifies potential therapeutic targets.
研究领域:
毒理学
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分子生物学
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细胞生物学
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环境科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Aggregate
·
2024
·
IF 13.9
Aihui Wang,Liqun Li,Liqian Zheng,Bang-Ping Jiang,Yihao Liu,Rimei Huang,Huimin Qiu,Shichen Ji,Hong Liang,Xing-Can Shen
Antibacterial lysozyme hydrogels show attractive advantages in wound dressings due to their intrinsic antibacterial activity and excellent biochemical and mechanical properties. Unfortunately, the development of such hydrogels is still greatly limited due to the lack of universal gelation strategies. Herein, a universal gelation strategy between lysozyme-nanofiber (LZF) and inorganic salts is proposed for the first time to construct functional nanofibrous lysozyme-based hydrogels. In particular, divalent anions are found to universally drive LZF for the aggregation and transformation into three-dimensional nanofibrous network hydrogels via electrostatic interaction, and the key role of divalent anions in the gelation is further proved by molecular dynamics simulation. In addition, near-infrared light-mediated photothermal characteristics are endowed with LZF to enhance its inhibitory activity of multidrug-resistant bacteria by the skeleton modification with genipin to produce genipin-conjuagted LZF (GLZF). As a distinct application paradigm, the brilliant immunomemory MnSO 4 -crosslinked GLZF hydrogel is constructed to sensitize the cGAS-STING pathway and skillfully establish an antibacterial immune microenvironment. It can excellently realize the anti-recurrence of diabetic wound infection via photo-enhanced bacterial killing and the cGAS-STING pathway. Thereby, it paves the way to employ the universal divalent anion-mediated gelation strategy for the future development of functional inorganic salt hybrid lysozyme hydrogels.
研究领域:
材料科学
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生物材料
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生物医学工程
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免疫学
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伤口愈合
✓ 已验证
产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Xueqin Zhu,Xiaoxi Wang,Zimai Liu,Bing Jiang,Zonghong He,Sijia Liu,Yahong Wu,Zixian Wu,Tiantian Zhang,Meiyi Liu,Kai Li,Xiaoshuang Niu,Yanfeng Gao
Although numerous peroxidase (POD)-like nanozymes have been designed for catalytic therapy of cancer, development of nanozymes with higher therapeutic efficacy and less adverse effects are challengeable. More importantly, the underlying antitumor mechanism remains largely unknown which hinders their application. Here, the nitrogen-doped carbon nanozyme (N-PCNS) as a model is utilized and demonstrated that its capacity to specifically activate the STING pathway in tumor cells through reactive oxgen species (ROS)-mediated mitochondrial DNA (mtDNA) release, which provides the initial signals for STING-dependent innate immune response. Further, a peptide-nanozyme conjugate (PNEC, OPBP1-N-PCNS), comprising a PD-L1 blocking/targeting dual-functional peptide and a cationic-coated N-PCNS is constructed, which are conjugated through a matrix metalloproteinase responsive peptide linker. The cleaved derivate nanozyme with positive charge exhibits recyclable capacity and superior ability in capturing and enhancing the transcellular transport of tumor-derived mtDNA toward DCs, thereby amplifying the STING signaling-mediated anti-tumor immune response. This study proposed a unique mechanism and design strategy for POD-like nanozyme in cancer immunotherapy.
研究领域:
癌症免疫治疗
·
纳米技术
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免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Advanced Science
·
2024
·
IF 14.3
Yuxuan Peng,Shuang Liang,Dan Liu,Kongshuo Ma,Kaiqing Yun,Mengli Zhou,Linna Hai,Mengdi Xu,Yiyang Chen,Zhaohui Wang
The highly immunosuppressive tumor microenvironment (TME) restricts the efficient activation of immune responses. To restore the surveillance of the immune system for robust activation, vast efforts are devoted to normalizing the TME. Here, a manganese-doped layered double hydroxide (Mn-LDH) is developed for potent anti-tumor immunity by reversing TME. Mn-LDH is synthesized via a one-step hydrothermal method. In addition to the inherent proton neutralization capacity of LDH, the introduction of manganese oxide endows LDH with an additional ability to produce oxygen. Mn-LDH effectively releases Mn 2+ and Mg 2+ upon exposure to TME with high levels of H + and H 2 O 2 , which activates synthase-stimulator of interferon genes pathway and maintains the cytotoxicity of CD8 + T cells respectively, achieving a cascade-like role in innate and adaptive immunity. The locally administered Mn-LDH facilitated a “hot” network consisting of mature dendritic cells, M1-phenotype macrophages, as well as cytotoxic and helper T cells, significantly inhibiting the growth of primary and distal tumors. Moreover, the photothermal conversion capacity of Mn-LDH sparks more robust therapeutic effects in large established tumor models with a single administration and irradiation. Overall, this study guides the rational design of TME-modulating immunotherapeutics for robust immune activation, providing a clinical candidate for next-generation cancer immunotherapy.
研究领域:
癌症免疫学
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纳米技术
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治疗开发
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免疫治疗
·
肿瘤微环境
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2023
·
IF 8.8
Yingqi Liu,Xuemei Yao,Youbo Zhao,De Fang,Lei Shi,Li Yang,Guanbin Song,Kaiyong Cai,Liqi Li,Qin Deng,Menghuan Li,Zhong Luo
The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.
研究领域:
癌症生物学
·
免疫学
·
细胞生物学
·
生物物理学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Kaiyuan Liu,Pengfei Zan,Zihua Li,Hengli Lu,Peng Liu,Li Zhang,Hongsheng Wang,Xiaojun Ma,Feng Chen,Jing Zhao,Wei Sun
The immunosuppressive tumor microenvironment (ITME) of osteosarcoma (OS) poses a significant obstacle to the efficacy of existing immunotherapies. Despite the attempt of novel immune strategies such as immune checkpoint inhibitors and tumor vaccines, their effectiveness remains suboptimal due to the inherent difficulty in mitigating ITME simultaneously from both the tumor and immune system. The promotion of anti-tumor immunity through the induction of immunogenic cell death and activation of the cGAS-STING pathway has emerged as potential strategies to counter the ITME and stimulate systemic antitumor immune responses. Here we present a bimetallic polyphenol-based nanoplatform (Mn/Fe-Gallate nanoparticles coated with tumor cell membranes, MFG@TCM) which combines with mild photothermal therapy (PTT) for reversing ITME via simultaneously inducing pyroptosis in OS cells and activating the cGAS-STING pathway in dendritic cells (DCs). The immunostimulatory pathways, through the syngeneic effect, exerted a substantial positive impact on promoting the secretion of damage-associated molecular patterns (DAMPs) and proinflammatory cytokines, which favors remodeling the immune microenvironment. Consequently, effector T cells led to a notable systemic antitumor immune response, effectively inhibiting the growth of both primary and distant tumors. This study offers a comprehensive approach to treat OS by mild photothermal therapy and modulating the immune microenvironment, exhibiting considerable potential in addressing the constraints associated with current therapeutic modalities. This article is protected by copyright. All rights reserved
研究领域:
癌症治疗
·
免疫学
·
纳米技术
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Jie Lei,Weifeng Zhang,Liang Ma,Yaqi He,Huaizhen Liang,Xiaoguang Zhang,Gaocai Li,Xiaobo Feng,Lei Tan,Cao Yang
The therapeutic effect of cancer immunotherapy is restrained by limited patient response rate caused by ‘cold’ tumors with an intrinsically immunosuppressive tumor microenvironment (TME). Activating stimulator of interferon genes (STING) confers promising antitumor immunity even in ‘cold’ tumors, but the further promotion of STING agonists is hindered by undesirable toxicity, low specificity and lack of controllability. Herein, an ultrasound-controllable cGAS-STING amplifying nanoagonist was constructed by coordinating mitochondria-targeting ligand triphenylphosphonium (TPP) to sonodynamic cobalt organic framework nanosheets (TPP@CoTCPP). The Co ions specifically amplify STING activation only when cytosolic mitochondrial DNA leakage is caused by sonocatalysis-induced ROS production and sensed by cGAS. A series of downstream innate immune proinflammatory responses induced by local cGAS-STING pathway activation under spatiotemporal ultrasound stimulation efficiently prime the antitumor T-cell response against bone metastatic tumor, a typical immunosuppressive tumor. We also found that the coordination of TPP augments the sonodynamic effect of CoTCPP nanosheets by reducing the band gap, improving O 2 adsorption and enhancing electron transfer. Overall, our study demonstrates that the targeted and amplified cGAS-STING activation in cancer cell controlled by spatiotemporal ultrasound irradiation boosts high-efficiency sonodynamic-ionicimmunotherapy against immunosuppressive tumor.
研究领域:
癌症免疫疗法
·
纳米技术
·
生物医学工程
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Inflammation Research
·
2022
·
IF 4.631
Renhui Huang,Qi Shi,Shutian Zhang,Hong Lin,Chengzhi Han,Xinyi Qian,Yijun Huang,Xiaorong Ren,Jiayuan Sun,Nana Feng,Chunmei Xia,Meng Shi
Purpose: Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS.Methods: We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system.Results: In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats.Conclusion: Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.
研究领域:
免疫学
·
病理生理学
·
呼吸医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Xiangling Zhang,Dongsheng Tang,Haihua Xiao,Bin Li,Kun Shang,Dan Zhao
Recent research has demonstrated that activating the cGAS-STING pathway can enhance interferon production and the activation of T cells. A manganese complex, called TPA-Mn, was developed in this context. The reactive oxygen species (ROS)-sensitive nanoparticles (NPMn) loaded with TPA-Mn are developed. NPMn activates the cGAS-STING pathway via cGAS activation (i.e., 1.6-fold enhancement of P-STING), which in turn increases the secretion of pro-inflammatory cytokines (e.g., TNF-α, IL-6, and IL-2). This promotes dendritic cell maturation, enhances the infiltration of cytotoxic T lymphocytes, and reduces the percentage of immunosuppressive regulatory T cells. In addition, it is crucial to emphasize that cisplatin-induced DNA damage can potentially trigger activation of the cGAS-STING pathway. NPMn, in combination with low-dose NPPt, a carrier of a Cis(IV) prodrug capable of causing DNA damage, augments the cGAS-STING pathway activation and significantly activates the tumor immune microenvironment (TIME). Furthermore, combined with anti-PD-1 antibody, NPPt+NPMn shows synergistic efficacy in both ovarian cancer peritoneal metastases and recurrence models. It not only effectively eliminates tumors but also induces a strong immune memory response, providing a promising strategy for the clinical management of ovarian cancer. This work offers a design of manganese-based nanoparticles for immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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