JOURNAL OF CONTROLLED RELEASE
·
2021
·
IF 9.776
Chao Wang,Zhaoyi Sun,Chenxuan Zhao,Zhewei Zhang,Haoran Wang,Yang Liu,Yunfei Guo,Bingtao Zhang,Lihong Gu,Yue Yu,Yiqiao Hu,Jinhui Wu
Radiotherapy (RT)-induced DNA damage leaked into cytosol can elicit host antitumor immune response. However, such response rate is unpromising due to limited cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA, which could be digested inherently by host DNases . Here we show that synchronizing Mn 2+ delivery with accumulated cytosolic DNA after RT can promote the activation of cGAS-STING pathway, thereby enhancing RT-induced antitumor immunity. Intratumoral Mn 2+ injection immediately after RT cannot enhance RT, while intratumoral Mn 2+ injection 24 h after RT can. Direct-injected Mn 2+ can be metabolized out from tumor in minutes while RT-induced DNA damage need cells mitotic progression for up to 24 h to accumulate into cytosol. Alginate can maintain Mn 2+ in tumor for up to 24 h due to it can chelate divalent cations . When the release profile of Mn 2+ is controlled by alginate (Alg) and synchronized with the accumulation of RT-induced DNA damage, over 90% inhibition rate can be obtained even in the unirradiated tumor, and survival time is significantly extended. This synchronizing strategy provides a simple and novel approach to effectively activate cGAS-STING pathway in tumor and promote RT-induced immunity.
研究领域:
肿瘤学
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免疫学
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放射生物学
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DOI
PubMed
高影响因子
Communications Biology
·
2024
·Vol. 7
·期 1
·1-11
·
IF 5.2
Qin Danhui,Song Hui,Wang Caiwei,Ma Xiaojie,Fu Yu,Zhao Chunyuan,Zhao Wei,Zhang Lei,Zhang Weifang
Stimulator of interferon genes (STING) is vital in the cytosolic DNA-sensing process and critical for initiating the innate immune response, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases. Zinc finger CCCH-type antiviral protein 1 (ZC3HAV1) specifically binds the CpG dinucleotides in the viral RNAs of multiple viruses and promotes their degradation. ZAPS (ZC3HAV1 short isoform) is a potent stimulator of retinoid acid-inducible gene I (RIG-I) signaling during the antiviral response. However, how ZC3HAV1 controls STING signaling is unclear. Here, we show that ZC3HAV1 specifically potentiates STING activation by associating with STING to promote its oligomerization and translocation from the endoplasmic reticulum (ER) to the Golgi, which facilitates activation of IRF3 and NF-κB pathway. Accordingly, Zc3hav1 deficiency protects mice against herpes simplex virus-1 (HSV-1) infection- or 5,6-dimethylxanthenone-4-acetic acid (DMXAA)-induced inflammation in a STING-dependent manner. These results indicate that ZC3HAV1 is a key regulator of STING signaling, which suggests its possible use as a therapeutic target for STING-dependent inflammation.
研究领域:
免疫学
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病毒学
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炎症性疾病
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DOI
PubMed
高影响因子
Science Bulletin
·
2025
·
IF 21.1
Fangke Zhang,Jiancheng Zheng,Fei Wang,Yaping Zhuang,Yunkai Tang,Juan Wang,Yawei Du,Wei-Li Zhao,Min Lu,Weiguo Hu,Wenguo Cui
Mutations in cytoplasmic DNA-degrading enzymes can lead to the accumulation of cytoplasmic DNA (cytoDNA), which excessively activates DNA-sensing pathways and exacerbates inflammatory aging. Reducing cytoDNA levels to suppress DNA-sensing mechanisms is therefore critical for treating elderly-onset rheumatoid arthritis (EORA). In this study, we constructed Trex1 mRNA loaded lipid nanoparticles (LNPs) via microfluidics and prepared DNase I loaded polydopamine (PDA) nanoparticles through oxidative polymerization. These two components were co-encapsulated into methacrylated hyaluronic acid (HAMA) microspheres using microfluidic photopolymerization. The LNPs incorporate cationic lipids to facilitate mRNA loading and promote endosomal escape, enabling efficient translation of TREX1 and subsequent recognition and degradation of cytoDNA. Meanwhile, cationic mesoporous polydopamine electrostatically adsorbs and degrades extracellular DNA. The microspheres function as a reservoir for sustained nanoparticle release, enabling synergistic inhibition of DNA sensing pathways. This microsphere based vaccine upregulates TREX1 expression in antigen-presenting cells (APCs) and reduces cytoDNA levels, thereby suppressing overactivation of the cGAS-STING signaling axis and promoting immune tolerance. It also attenuates the differentiation of CD4+ T cells into Th1, Th2, Th17, and Treg subsets. In an aged rat model of rheumatoid arthritis, the vaccine alleviated soft tissue swelling, synovitis, and cartilage and bone damage. By clearing excess cytoDNA and restraining DNA-sensing hyperactivation, this vaccine induces cellular immune tolerance and represents a promising therapeutic strategy for rheumatoid arthritis in the elderly.
研究领域:
免疫学
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纳米医学
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分子生物学
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疫苗学
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风湿病学
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衰老研究
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基因治疗
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yanmei Li,Junmei Nie,Xinyu Li,Ni Yan,Renjiang Kong,Jiaqi Huang,Yeyang Wu,Zhuofeng Li,Yingtao Zhong,Xin Chen,Hong Cheng
Stimulator of interferon genes (STING) plays an essential role in initiating the innate anti-tumor immunity, which could be activated by the cytosolic DNA but suppressed by the immunosuppressive cells. In this work, a self-delivery ternary immunostimulant (designated as ImmSt) is fabricated for colorectal cancer therapy with the immunological cascades of photodynamic DNA damage and T regulatory cell inhibition. Among which, the photosensitizer of Chlorin e6 (Ce6), the STING agonist of 5,6-dimethylxanthine-4-acetic acid (DMXAA) and the phosphatidylinositol 3-kinases (PI3Ks) inhibitor of ZSTK474 could self-assemble into uniform nanomedicine without drug excipient, which enhances the drug stability, bioavailability and pharmacological activities. Importantly, the photodynamic therapy (PDT) effect of ImmSt produces enormous reactive oxygen species to ablate tumor cells, and also triggers the release of cytosolic DNA to amplify the STING signal in combination with the STING agonist. Moreover, ImmSt is able to induce a systemic anti-tumor immunity by the cascade activation of T cells and the decrease of T regulatory cells. In vitro and in vivo results confirm that ImmSt can efficiently eradicate colorectal cancer without severe side effects, which may provide a sophisticated mechanism for immunotherapy in consideration of the immune activation and immunosuppressive factors.
研究领域:
肿瘤学
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免疫疗法
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药理学
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纳米技术
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分子生物学
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产品关联
DOI
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2022
·Vol. 32
·期 17
·2108883
·
IF 19.924
Xiu Zhao,Kaixiang Zhang,Yiyang Wang,Wenxiao Jiang,Hui Cheng,Qiongwei Wang,Tingting Xiang,Zhenzhong Zhang,Junjie Liu,Jinjin Shi
Efficient nuclear DNA damage and release is highly recommended to improve the photodynamic immunotherapy by eliciting innate immune response yet remains challenging. Herein, an intracellular self-assembly driven nucleus-targeted photo-immune stimulator (PIS) with chromatin decompaction function is reported for innate and adaptive antitumor immunity co-activation. The PIS consists of vorinostat (SAHA)-loaded manganese-porphyrin metal-organic framework (Mn (III)-TCPP MOF) with further modification of AS1411 aptamer. The PIS can be efficiently internalized by tumor cells and disassembled under the intracellular overexpressed glutathione (GSH). Notably, the released AS1411 is able to be self-assembled with photosensitizer TCPP in situ within cells, driving nucleus-targeted delivery of TCPP; meanwhile, the loaded SAHA can induce chromatin decompaction, cooperatively promoting TCPP-mediated photodynamic nuclear DNA damage and cytosolic release under laser irradiation. In addition, the released manganese ions (Mn 2+ ) further enhance the cytosolic DNA/cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway mediated innate immunity, which synergizes with PDT-induced immunogenic cell death to achieve co-activation of innate and adaptive immunity. Compared to traditional PDT, the self-assembly driven nucleus-targeted PDT system with chromatin decompaction show significantly enhanced efficacy for inhibiting primary tumor growth and distant metastasis in several xenograft tumor models, mechanistically by promoting the maturation of dendritic cells and tumor infiltration of natural killer cell, cytotoxic T lymphocytes.
研究领域:
癌症研究
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免疫学
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药学
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纳米技术
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生物医学工程
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产品关联
DOI
高影响因子
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