ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Mengna Dong,Chan Xue,Xinhui Yang,Hongfang Liu,Hong Wang,Yonggui Liao,Yajiang Yang,Xiangliang Yang,Qin Wang
cGAS-STING pathway, an important innate immune signaling pathway, has attracted extensive attention in anti-tumor immunotherapy research. However, the limited delivery ratio of STING agonists and lactate-induced lactylation present significant challenges in advancing cGAS-STING antitumor immune response. Herein, natural anaerobic sulfate-reducing bacteria (SRB) are utilized as a biofactory to in situ biosynthesize MnS nanoparticles (MnS@SRB) for amplifying MnS-activated cGAS-STING anti-tumor immune responses through continuous lactate depletion by SRB. After intravenous injection, MnS@SRB can actively migrate to tumor tissues via SRB-mediated hypoxia targeting, further continually release H 2 S and Mn 2+ in the acidic tumor microenvironment. H 2 S stimulates mitochondrial dysfunction and induces mitochondrial DNA leakage, which is then recognized by cGAS to activate STING signaling pathway. Mn 2+ further augments STING-mediated secretion of type I interferons and inflammatory factors. Importantly, MnS@SRB can effectively metabolize lactate in tumors, thereby alleviating cGAS lactylation for amplifying cGAS-STING immune response and regulating macrophage phenotype to M1-type, reducing the tumor-infiltrating regulatory T cells and increasing CD8 + T cells level, further enhancing both adaptive and innate immunosurveillance. As a result, MnS@SRB effectively inhibite the tumors growth and metastasis. Therefore, MnS@SRB-based delivery system enables efficient cGAS activator delivery and tumor immunosuppressive microenvironment remodeling, thereby opening a new avenue for synergistically enhanced STING activation.
研究领域:
生物医学工程
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免疫学
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肿瘤学
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产品关联
DOI
高影响因子
Biomaterials Science
·
2025
·
IF 5.7
Xinyu Wang,Qingbin He,Lining Wang,Chengzhilin Li,Wenyu Zhang,Zhonghou Rong,Qingqing Yin,Yingchun Zhao
Sepsis, an inflammatory disease caused by bacterial infection, has become a global public health crisis. Excessive reactive oxygen species (ROS) in sepsis patients act as the primary trigger for activating intracellular immune pathways, ultimately leading to multiple organ dysfunction syndrome. The overexpression of acidic metabolites and ROS, characteristic of the infected microenvironment, significantly impedes sepsis treatment. Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, plays a key role in inflammatory diseases. The detrimental effects of STING in sepsis have been well documented. Here, we developed a pH-responsive nanotherapy platform (DMSNM@C-178/PAA) that combines ROS scavenging with cGAS-STING pathway inhibition for anti-inflammatory therapy. This nanoparticle is selectively released in the infected microenvironment, where reduced molybdenum-based polyoxometalates (Mo-POM) efficiently neutralize toxic ROS in vivo, while C-178 selectively inhibits the cGAS-STING pathway, thereby attenuating the inflammatory response and preventing organ deterioration. In vitro and in vivo studies demonstrate that DMSNM@C-178/PAA treats sepsis by eliminating excess ROS and modulating autoimmune dysfunction via the cGAS-STING pathway, providing a novel therapeutic strategy for sepsis management.
研究领域:
医学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Nailin Yang,Shumin Sun,Jiachen Xu,Fei Gong,Huali Lei,Yu Hao,Zifan Pei,Chenya Wang,Qiao Yu,Jihu Nie,Nan Jiang,Caifang Ni,Liang Cheng
The cGAS-STING pathway is pivotal in initiating antitumor immunity. However, tumor metabolism, particularly glycolysis, negatively regulates the activation of the cGAS-STING pathway. Herein, Mn galvanic cells (MnG) are prepared via liquid-phase exfoliation and in situ galvanic replacement to modulate tumor metabolism, thereby enhancing cGAS-STING activation for bidirectional synergistic H 2 -immunotherapy. The obtained MnG can be etched by water, enabling efficient and sustained generation of H 2 gas and Mn 2+ . MnG not only activated and amplified the cGAS-STING pathway through the sustained release of Mn 2+ but also regulated tumor glucose metabolism to inhibit the expression of three prime repair exonuclease 2 (TREX2), thereby synergistically enhancing the activation of the cGAS-STING pathway. The injection of MnG into tumors resulted in a robust immune response, thereby providing favorable support for antitumor therapy. Consequently, the combination of MnG with immune checkpoint blockade therapy resulted in significant suppression of both primary tumors and distant tumors. Furthermore, the MnG-lipiodol dispersion exhibited remarkable efficacy in combination with transarterial embolization (TAE)-gas-immunotherapy in a rabbit orthotopic liver tumor model. The present study underscores the significance of employing a metal galvanic cell strategy for enhanced immunotherapy, thereby offering a novel approach for rational design of bioactive materials to augment immunotherapeutic effectiveness.
研究领域:
肿瘤学
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免疫学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2025
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IF 9.6
Hua Chai,Renpeng Xia,Nan Ouyang,Jingyu Yao,Jiukun Hu,Minxuan Sun,Peng Miao
Reactive oxygen species (ROS) mediated cell damage is one of the most popular and effective ways for cancer therapy. However, overexpressed antioxidant of reduced glutathione (GSH) is always activated in tumor cells, which maintains redox equilibrium. Attempts to deplete GSH and elevate ROS levels can be potent therapeutic strategies. Herein, tumor cell membrane-encapsulated Fe 3 O 4 @MnO and 2′,3′-cyclic GMP-AMP (cGAMP) are prepared as the nanocatalyst for cancer therapy. The ionized Fe 3+ /Fe 2+ redox couple is utilized to initiate the Fenton reaction. Intracellular GSH level can thus be efficaciously controlled, and peroxide oxidation is catalyzed to produce excessive ROS. Meanwhile, cGAMP is released to trigger the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling axis. This targeted activation enhances the recruitment of macrophages, stimulates the secretion of critical pro-inflammatory cytokines, and consequently bolsters the efficacy of innate immune responses within the tumor microenvironment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Xiao Xiao,Song Wang,Xin Zhang,Junyong Zheng,Dazhi Yang,Songlin Peng
The pollution issue of chlorinated paraffins has garnered widespread attention, with short-chain chlorinated paraffins (SCCPs) being comprehensively banned by the Stockholm Convention due to environmental contamination concerns. Currently, long-chain chlorinated paraffins (LCCPs) are widely used, necessitating an assessment of their toxicological impact. Bone marrow mesenchymal stem cells (MSCs) are a type of multipotent stem cell with self-renewal, immunoregulatory, and tissue repair capabilities, exhibiting important biological functions. In this study, MSCs were used as a model to evaluate the toxicological effects of LCCP. Initially, cell proliferation experiments were conducted to assess the impact of LCCP on MSC proliferation. The results indicated a significant reduction in cell proliferation capacity. Further work revealed that LCCP treatment induced cell senescence, as evidenced by Sa-β-gal staining and the evaluation of senescence markers, including p16, p21, and p53. Furthermore, LCCP treatment led to inflammation and oxidative stress, as analyzed by corresponding marker molecules, and ultimately resulted in cell death. Based on these findings, we investigated the molecular mechanisms underlying LCCP-induced MSC senescence. In summary, this paper is the first study to systematically investigate the toxicological effects of LCCPs on stem cells. The current study demonstrates that LCCP induces MSC senescence, highlighting its potential toxicity. This research lays the foundation for further elucidating the toxicology of LCCP. This finding suggests that the use of LCCPs should be strictly controlled under rigorous regulation.
研究领域:
毒理学
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细胞生物学
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环境科学
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DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
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IF 9.6
Nan Zhong,Ziyue Zu,Yishi Lu,Xuan Sha,Yang Li,Yang Liu,Shangyu Lu,Xi Luo,Yan Zhou,Jun Tao,Feiyun Wu,Zhaogang Teng,Yuxia Tang,Shouju Wang
Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway could effectively initiate antitumor immunity in triple-negative breast cancer. However, current nuclear DNA-mediated activation of STING pathway remains constrained by the tight protection of nuclear membrane and histones, highlighting the need for new strategies to enhance its efficacy. Mitochondrial DNA (mtDNA), in contrast, is more vulnerable to damage. Herein, our nanoplatforms exploited the high glutathione (GSH) environment characteristic of tumors to release abundant Mn 2+ , which induced mitochondrial dysfunction and the release of endogenous mtDNA. The released mtDNA, in conjunction with Mn 2+ itself functioning as a strong cGAS agonist, effectively activated cGAS-STING pathway. Consequently, the cGAS-STING-dependent secretion of type I interferon successively enhanced the maturation of dendritic cells and cross-priming of CD8 + T cells. In a poorly immunogenic 4T1 tumor model, TPP-MMONs efficiently primed systemic antitumor immunity and significantly enhanced the therapeutic efficacy of αPD-L1 therapy, suppressing tumor growth in both localized and metastatic tumor models. These findings provided an innovative and straightforward strategy to enhance TNBC immunogenicity by targeting mitochondrial damage to induce mtDNA-mediated cGAS-STING activation, thereby sensitizing tumors to immune checkpoint inhibitor therapy. Statement of Significance The cGAS-STING pathway is a promising target for overcoming immunoresistance in TNBC. However, current nuclear DNA-based activation strategies are limited by the tight protection of nuclear membrane and histones. Herein, we reported novel manganese-rich, mitochondria-targeting nanoplatforms (TPP-MMONs), which can release abundant Mn²⁺ and significantly induce mitochondrial dysfunction, leading to the release of mtDNA. As a result, the nanoplatforms can effectively stimulate the cGAS-STING pathway, thereby enhancing immune responses and improving the therapeutic efficacy of αPD-L1 therapy, offering new insights into TNBC treatments.
研究领域:
肿瘤学
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免疫学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2025
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IF 5.1
Jingxian Yang,Mengyao Chen,Ruihao Li,Yanting Sun,Pingting Ye,Kang Fang,Chunhui Wang,Shuo Shi,Chunyan Dong
The exclusion of immune cells from the tumor can limit the effectiveness of the immunotherapy in triple negative breast cancer (TNBC). The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a crucial role in priming adaptive anti-tumor immunity through type I interferons (IFNs) production, facilitating the maturation of dendritic cells (DCs) and the function of T cells. Although the increased programmed death-ligand 1 (PD-L1) expression upon STING activation is favorable for amplifying the efficacy of immune checkpoint inhibitors (ICIs) and realizing combination therapy, the penetration barrier remains a major obstacle. Herein, we fabricated a smart-responsive nanosystem (B&V@ZB-MCL) by integrating the extracellular matrix (ECM)-degrading drug losartan with STING agonist (Vadimezan, abbreviated as Vad) and PD-L1 inhibitor (BMS-1). Losartan was first released in the acidic tumor microenvironment to overcome physical barrier, enhancing the penetration of immunotherapeutic components. Under the triggering of 1O2 generated by photosensitizer (Ce6), the reactive oxygen species (ROS)-sensitive degradation of nanocore ensure the site-directed release of Vad and BMS-1. The released Vad and damaged tumor DNA activated immune responses through cGAS-STING pathway, while the elevated expression level of PD-L1 promoted the anti-tumor effect of BMS-1. Significant degradation of collagen fibers, restoration in immune effector cells, and lower tumor volume were observed in this integrating triple drug sequential therapy, which provides a promising prospect for the TNBC treatment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Xiaoyu Pan,Yan Lin,Chunlin Lin,Songyi Liu,Penghang Lin,Xiang Lin,Ruofan He,ZiChen Ye,Jianxin Ye,Guangwei Zhu
The cGAS-STING signaling pathway is a pivotal immune response mechanism that bridges tumor and immune cell interactions. This study describes a multifunctional LPDAM nanoplatform integrating Lapachone, polydopamine (PDA), and Mn 2+ , which synergistically kills tumor cells and activates the cGAS-STING pathway, thereby inducing DC maturation and T cell activation to achieve potent antitumor immunity. In the tumor microenvironment, Lapachone generates H 2 O 2 via the NAD(P)H:quinone oxidoreductase 1 (NQO1 enzyme), while Mn 2+ catalyze H 2 O 2 conversion into •OH through chemodynamic effects (CDT). The photothermal effects (PTT) of PDA further amplify this cascade reaction, producing reactive oxygen species (ROS) that damage tumor mitochondria and release mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING pathway, while Mn 2+ enhances the sensitivity of cGAS to mtDNA, leading to robust antitumor immunity. Concurrently, photothermal-induced immunogenic cell death (ICD) promotes d endritic cells ( DCs) maturation, further strengthening immune responses. Moreover, Mn 2 ⁺ also serves as a contrast agent for T1-weighted magnetic resonance imaging (MRI), offering precise tumor visualization. This study demonstrates that the LPDAM nanoplatform facilitates Lapachone/CDT/PTT synergistic therapy under MRI guidance, showcasing its potential as an innovative strategy for combined immunotherapy in clinical oncology.
研究领域:
肿瘤学
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免疫学
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纳米医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-16
·
IF 6.1
Xiong Yi,Chen Jiawen,Liang Wei,Li Kun,Huang Yingqi,Song Jingwen,Zhang Baoyu,Qiu Xiusheng,Qiu Dongbo,Zhang Qi,Qin Yunfei
Background Liver surgery during the perioperative period often leads to a significant complication known as hepatic ischemia-reperfusion (I/R) injury. Hepatic I/R injury is linked to the innate immune response. The cGAS-STING pathway triggers the activation of innate immune through the detection of DNA within cells. Nevertheless, the precise mechanism and significance of the cGAS-STING pathway in hepatic I/R injury are yet to be investigated. Methods Mouse model of hepatic I/R injury was used in the C57BL/6 WT mice and the STING knockout (STING-KO) mice. In addition, purified primary hepatocytes were used to construct oxygen-glucose deprivation reperfusion (OGD-Rep) treatment models. Results Our research revealed a notable increase in mRNA and protein levels of cGAS and STING in liver during I/R injury. Interestingly, the lack of STING exhibited a safeguarding impact on hepatic I/R injury by suppressing the elevation of liver enzymes, liver cell death, and inflammation. Furthermore, pharmacological cGAS and STING inhibition recapitulated these phenomena. Macrophages play a crucial role in the activation of the cGAS-STING pathway during hepatic I/R injury. The cGAS-STING pathway experiences a significant decrease in activity and hepatic I/R injury is greatly diminished following the elimination of macrophages. Significantly, we demonstrate that the activation of the cGAS-STING pathway is primarily caused by the liberation of mitochondrial DNA (mtDNA) rather than nuclear DNA (nDNA). Moreover, the safeguarding of the liver against I/R injury is also attributed to the hindrance of mtDNA release through the utilization of inhibitors targeting mPTP and VDAC oligomerization. Conclusions The results of our study suggest that the release of mtDNA plays a significant role in causing damage to liver by activating the cGAS-STING pathway during I/R injury. Furthermore, inhibiting the release of mtDNA can provide effective protection against hepatic I/R injury.
研究领域:
免疫学
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肝病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CHEMISTRY-A EUROPEAN JOURNAL
·
2025
·
IF 3.7
Fa Wang,Zhiyang Wang,Shuqi Huang,Jinrong Yang,Yu Chen,Hui Chao
Graphical A convenient strategy by synergistic delivering DNA and DNA photocleavage agents to tumor cells was developed for effective photodynamic immunotherapy under hypoxia. Plasmid DNAs intercalated with Ru(II) complexes were encapsulated in liposomes to create nano-photosensitizers. Upon light exposure, the ruthenium complex photo-cleavages DNA. The DNA fragments specifically stimulate the cGAS-STING pathway and induce immunogenic death. This study presents a convenient strategy for photodynamic immunotherapy against cisplatin-resistant tumor cells under hypoxia.
研究领域:
生物化学
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肿瘤学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Kehong Dong,Mei Zhang,Ying Liu,Xintao Gao,Xiaochen Wu,Dayong Shi,Chuanlong Guo,Jing Wang
Excessive acetaminophen (APAP) induces excess reactive oxygen species (ROS), leading to liver damage. Pterostilbene (PTE) has excellent antioxidant and anti-inflammatory activities, but poor solubility limits its biological activity. In this study, we prepared PTE-loaded Soluplus/poloxamer 188 mixed micelles (PTE-MMs), and the protective mechanism against APAP-induced liver injury was investigated. In vitro results showed that PTE-MMs protected H2O2-induced HepG2 cell proliferation inhibition, ROS accumulation, and mitochondrial membrane potential destruction. Immunofluorescence results indicated that PTE-MMs significantly inhibited H2O2-induced DNA damage and cGAS-STING pathway activation. For in vivo protection studies, PTE-MMs (25 and 50 mg/kg) were administered orally for 5 days, followed by APAP (300 mg/kg). The results showed that APAP significantly induced injury in liver histopathology as well as an increase in serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, the above characteristics of APAP-induced acute liver injury were inhibited by PTE-MMs. In addition, APAP-induced changes in the activities of antioxidant enzymes such as SOD and GSH in liver tissue were also inhibited by PTE-MMs. Immunohistochemical results showed that PTE-MMs inhibited APAP-induced DNA damage and cGAS-STING pathway activation in liver tissues. For in vivo therapeutic effect study, mice were first given APAP (300 mg/kg), followed by oral administration of PTE-MMs (50 mg/kg) for 3 days. The results showed that PTE-MMs exhibited promising therapeutic effects on APAP-induced acute liver injury. In conclusion, our study shows that the Soluplus/poloxamer 188 MM system has the potential to enhance the biological activity of PTE in the protection and therapeutic of liver injury.
研究领域:
药剂学
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肝脏病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Xintao Gao,Tao Jiang,Xiaochen Wu,Yantao Li,Jun Xiao,Lin Long,Chuanlong Guo
Cervical cancer remains one of the leading causes of mortality among women, and immunotherapy targeting the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway holds promise for its treatment. This study has developed nanoparticles based on fucoidan (Fu/CA NPs), successfully loading them with caffeic acid (CA) for application in cervical cancer therapy. In vitro experiments revealed that Fu/CA NPs significantly inhibited the proliferation of cervical cancer HeLa cells (by 65.73 ± 4.06 %) and induced apoptosis through the accumulation of reactive oxygen species and mitochondrial damage. Furthermore, treatment with Fu/CA NPs activated the cGAS-STING pathway, attributed to the cytoplasmic release of mitochondrial DNA (mtDNA) and the induction of DNA double-strand breaks (dsDNA) by Fu/CA NPs. In vivo results confirmed that Fu/CA NPs suppressed solid tumor growth (by 67.8 %), with even more pronounced antitumor effects observed when combined with cisplatin (96.5 %), a phenomenon also associated with the activation of the cGAS-STING pathway. Excitingly, the combination of Fu/CA NPs and cisplatin alleviated cisplatin-induced nephrotoxicity, as indicated by a decrease in blood urea nitrogen (BUN) by 53.27 % and serum creatinine (SCr) by 74.93 %. In summary, our research presents a potential therapeutic avenue for cervical cancer treatment, particularly highlighting the synergistic benefits of combining Fu/CA NPs with cisplatin.
研究领域:
肿瘤学
·
药理学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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