BIOMATERIALS
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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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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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PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8049
·
IF 13.3
Jiaorong Qu,Jianan Li,Le Wang,Yufei Li,Yinqiang Zhang,Jingtao Li,Zixuan Huo,Junsong Han,Runping Liu,Guifang Fan,Yinhao Zhang,Xiaoyong Xue,Xiaojiaoyang Li
Background and aims: Inducing the senescence of activated hepatic stellate cells (HSCs) has emerged as a promising therapeutic strategy for liver fibrosis, with potential connections to the Yes-associated protein (YAP)-controlled cGAS-STING pathway. However, the regulatory role of cytoskeletal dynamics on HSC senescence and its potential as a target for natural products have remained poorly understood. Methods: We employed preclinical in vivo and in vitro transcriptome analyses, experimental systems, Tmem173 -/- mice and liver-specific STING knockdown mice to demonstrate the anti-fibrotic effects and mechanism of ligustilide (LIG). Results: LIG selectively bound to monomeric globular actin (G-actin), thereby preventing its polymerization into polymeric filamentous actin (F-actin), which disturbed its interaction with intermediate filament component lamin A/C and initially destroyed the nuclear membrane. Moreover, the disruption of nuclear membrane caused YAP leakage from nuclear, which in turn suppressed lamin A/C and created a deleterious feedback loop that exacerbated nuclear membrane destabilization. Consequently, nuclear double stranded DNA (dsDNA) leakage caused by the above damage cascade ultimately triggered the activation of the cGAS-STING signaling pathway, promoting senescence-associated secretory phenotypes (SASPs) release and inducing HSC senescence. Moreover, the induction of HSC senescence and anti-fibrotic effects of LIG were completely abrogated in both whole-body STING knockout and liver-specific STING knockdown mice. Conclusions: By interacting with G-actin, LIG disrupted the cytoskeleton to compromise nuclear integrity with the involvement of YAP and further stimulated the cGAS-STING pathway, leading to the release of SASPs and HSC senescence, which ultimately mitigated liver fibrosis.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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生物化学
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Kunguo Liu,Shiyu Du,Jiawei Yang,Juanjuan Li,Shijie Wang,Zhibin Zhang,Wen Luo,Chao Chen,Jingjing Yang,Xin Han
The immunosuppressive tumor microenvironment (TME) in solid tumors often impedes the efficacy of immunotherapy. Bacterial outer membrane vesicles (OMVs), as a promising cancer vaccine that can potently stimulate immune responses, have garnered interest as a potential platform for cancer therapy. However, the low yield of OMVs limits their utilization. To address this limitation, we developed a novel approach to synthesize OMV-like multifunctional synthetic bacterial vesicles (SBVs) by pretreating bacteria with ampicillin and lysing them through sonication. Compared to OMVs, the yield of SBVs increased by 40 times. Additionally, the unique synthesis process of SBVs allows for the encapsulation of bacterial intracellular contents, endowing SBVs with the capability of delivering catalase (CAT) for tumor hypoxia relief and activating the host cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway. To overcome the toxicity of lipopolysaccharide (LPS) on the SBVs surface, we decorated SBVs with a biocompatible polydopamine (PDA) shell, which allowed TME reprogramming using SBVs to be conducted without adverse side effects. Additionally, the photosensitizer indocyanine green (ICG) was loaded into the PDA shell to induce immunogenic cell death and further improve the efficacy of immunotherapy. In summary, the SBVs-based therapeutic platform SBV@PDA/ICG (SBV@P/I) can synergistically elicit safe and potent tumor-specific antitumor responses through combined immunotherapy and phototherapy.
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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DOI
PubMed
高影响因子
Small
·
2025
·
IF 12.1
Jinglang Gong,Hongxiang Huang,Maoyu Gao,Yiling Ruan,Ruifang Chen,Yaoting Li,Shouju Wang,Xiaolian Sun
Nanometal-based therapies face challenges arising from the overexpression of proton efflux transporters in cancer cells, which acidifies the extracellular tumor microenvironment (TME) while preserving a relatively neutral intracellular pH, thereby compromising therapeutic efficacy and fostering an immunosuppressive TME. Here, we integrate the proton pump inhibitor pantoprazole (PTZ) with manganese ferrite nanoparticles (MFNs) within an acidity-responsive polymer for enhanced ferroptosis and cGAS-STING activation mediated immunotherapy. This assembly (PTZ/MFNAs) facilitates tumor accumulation through the enhanced permeability and retention effect while initially restricting the release of metal ions. Upon reaching the tumor site, PTZ release increases intracellular acidity, which further triggers assembly disintegration, accelerates the release of iron and manganese ions, and neutralizes the extracellular microenvironment to alleviate immunosuppression. The released manganese ions synergistically collaborate with iron ions to amplify reactive oxygen species (ROS) generation for ferroptosis while activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, stimulating innate immunity. This potentiation of innate immunity, coupled with the reversal of TME immunosuppression, collectively and effectively inhibits tumor growth and metastasis. Therefore, the PTZ/MFNAs co-delivery system represents a promising pH-modulation strategy to enhance iron/manganese ions-mediated ferroptosis and cGAS-STING activation-induced immunotherapy.
研究领域:
纳米医学
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癌症免疫治疗
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肿瘤微环境
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活性氧信号传导
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铁死亡研究
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DOI
PubMed
高影响因子
MATERIALS & DESIGN
·
2026
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IF 8.2
Yuanxiang Yu,Wenjing Li,Yu Shao,Hairui Tian,Tingting Deng,Meili Li,Jiarui Li,Xuanhuan Ma,Zhenhao Li,Cong Huang,Wei Jiang,Xiaoxiao Luo
A phase-change nanocomposite enables light-triggered multimodal therapy and tumor-localized cisplatin release. • Photothermal and photodynamic stress induces mitochondrial DNA damage and cytosolic DNA sensing. • Innate immune activation drives immunogenic cell death, dendritic cell priming, and CD8+ T-cell infiltration. • The treatment achieves durable control and helps overcome immune resistance in triple-negative breast cancer. Activation of the GMP/AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway can sensitize tumors to immunotherapy, yet conventional photothermal therapy (PTT) or photodynamic therapy (PDT) alone rarely generates enough cytosolic double-stranded DNA (dsDNA) to fully engage this axis. Here we develop phase-change lauric-acid nanocomposites (CCL NPs) that co-load photothermal Cu 2-X S nanoparticles and cisplatin. After cellular uptake, near-infrared (NIR) irradiation induces synergistic PTT/PDT, and NIR-II heating melts the lauric-acid shell to trigger on-demand cisplatin release within tumors. The resulting ROS burst together with cisplatin causes extensive mitochondrial DNA damage and dsDNA leakage into the cytosol, leading to robust cGAS/STING activation. In tumor-bearing mice, CCL NPs promote dendritic-cell maturation and antigen cross-presentation, increase cytotoxic T-lymphocyte infiltration, and elicit immunogenic cell death, achieving durable tumor suppression with minimal systemic toxicity. Released copper further contributes via cuproptosis. Overall, CCL NPs integrate controllable chemotherapy with PTT/PDT to amplify innate immune sensing and drive effective antitumor immunity. Download: Download high-res image (164KB) Download: Download full-size image
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-17
·
IF 12.6
Bai Ge,Liu Hongwen,Li Wei,Chen Sijia,Wang Lishan,Wang Zhangding,Zhou Yue,Pan Yani,Liu Yu,Chen Qi,Zhang Nannan,Wei Jingjing,Fu Xueni,Zhou Yaru,Zhu Yun,Xu Lei,Wang Lei
Background The remodeling of extracellular matrix often fails chemotherapeutic agents to fight intrahepatic cholangiocarcinoma (ICC). The cGAS/STING pathway can trigger the innate immune response to obtain better immunotherapeutic outcomes. Results A cLipG/CuET nanocomposite was designed and synthesized based on glycyrrhizic acid (GA) and copper diethyldithiocarbamate (CuET). GA can open mitochondrial permeability transition pores (MPTPs), allowing Cu (II) to interrupt mitochondrial function through copper toxicity. By activating the cGAS-STING signaling pathway in macrophages, this mitochondrial-targeting polymer (cLipG/CuET) significantly boosted the production of mitochondrial reactive oxygen species (mtROS), and promoted the escape of damaged mitochondrial DNA (mtDNA) from ICC cells. Consequently, M1 polarization of cancer-associated macrophages enhanced the immune response against ICC. In the mouse model, the intravenous administration of cLipG/CuET transformed the ICC from “cold” into “hot”. Conclusions With a high biosafety, cLipG/CuET exerted a synergistic effect on the immune checkpoint inhibitor αCTLA-4 against ICC, and their combination provided a new therapeutic strategy. Graphical abstract
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高影响因子
BIOSCIENCE REPORTS
·
2026
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IF 4.5
Ma Runtao,Song Yue,Zhang Lijun,Wang Peng,Chen Jiaqi,Chen Tianqi,Zhu Guangyao,Pan Qingrong,Ma Mengyu,Mo Qigui,Lu Surui,Yu Xuanjie,Guo Yi
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and is closely linked to chronic inflammation. This study examined how the β-adrenergic receptor agonist isoprenaline (ISO) protected against DKD by regulating the cGAS–STING signaling pathway through multiple targets. In a streptozotocin-induced diabetic mouse model, ISO treatment improved glomerulosclerosis, reduced podocyte injury and proteinuria, and suppressed renal inflammation. Network pharmacology and molecular docking suggested that, besides activating ADRB1/2, ISO may interact with AKT1, SRC, GSK3β, and EGFR, which are involved in cGAS–STING signalling regulation. These findings indicate that ISO alleviates DKD by inhibiting excessive activation of the cGAS–STING pathway through multi-target coordination, providing a new perspective for therapeutic development.
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DOI
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Peng Wang,Yinfeng Wang,Huimin Li,Miaomiao Wang,Yue Wang,Xiaofei Wang,Lang Ran,Huan Xin,Jingyi Ma,Geng Tian,Wenjuan Gao,Guilong Zhang
Herein, we developed a doxorubicin (Dox)-loaded and 4T1 cancer cell membrane-modified hydrogenated manganese oxide nanoparticles (mHMnO-Dox) to elicit systemic antitumor immune responses. The results revealed that mHMnO-Dox actively recognized tumor cells and then effectively delivered Dox into the cells. Upon entering tumor cells, the mHMnO-Dox underwent rapid degradation and abundant release of Mn 2+ and chemotherapeutic drugs. The released Mn 2+ not only catalysed a Fenton-type reaction to produce excessive reactive oxygen species (ROS) but also activated the cGAS-STING pathway to boost dendritic cell (DC) maturation. This process increased cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment into the tumor site. In addition, the released Dox could contribute to a chemotherapeutic effect, while activating DC cells and subsequently intensifying immune responses through immunogenic cell death (ICD) of tumor cells. Consequently, the mHMnO-Dox suppressed the primary and distal tumor growth and inhibited tumor relapse and metastasis, as well as prolonged the lifespan of tumor-bearing mice. Thus, the mHMnO-Dox multimodally activated DC cells to demonstrate synergistic antitumor activity, which was mediated via the activation of the cGAS-STING signalling pathway to regulate tumor microenvironment, ICD-mediated immunotherapy and ROS-mediated CDT. These findings suggest the therapeutic potential of mHMnO-Dox in cancer immunotherapy. Statement of significance A cancer cell membrane-camouflaged hydrogenated mesoporous manganese oxide (mHMnO) has been developed as a cGAS-STING agonist and ICD inducer. The mHMnO effectively induced abundance of ROS production in cancer cells, which caused cancer cell death and then promoted DC maturation via tumour-associated antigen presentation. Meanwhile, the mHMnO significantly activated cGAS-STING pathway to facilitate DC maturation and cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment, which further enhanced tumour immune response. In addition, the combination of the mHMnO and Dox could synergistically promote tumour ICD and then multimodally induce DC maturation, achieving an enhanced CIT. Overall, this study provides a potential strategy to design novel immunologic adjuvant for enhanced CIT.
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高影响因子
Cell Death Discovery
·
2023
·Vol. 9
·期 1
·1-15
·
IF 7
Li Hong-Ying,Wei Ting-Ting,Zhuang Miao,Tan Cheng-Ye,Xie Tian-Hua,Cai Jiping,Yao Yong,Zhu Lingpeng
Cellular senescence is a hallmark of aging and has been linked to age-related diseases. Age-related macular degeneration (AMD), the most common aging-related retinal disease, is prospectively associated with retinal pigment epithelial (RPE) senescence. However, the mechanism of RPE cell senescence remains unknown. In this study, tert-butyl hydroperoxide (TBH)-induced ARPE-19 cells and D-galactose-treated C57 mice were used to examine the cause of elevated iron in RPE cell senescence. Ferric ammonium citrate (FAC)-treated ARPE-19 cells and C57 mice were used to elucidated the mechanism of iron overload-induced RPE cell senescence. Molecular biology techniques for the assessment of iron metabolism, cellular senescence, autophagy, and mitochondrial function in vivo and in vitro. We found that iron level was increased during the senescence process. Ferritin, a major iron storage protein, is negatively correlated with intracellular iron levels and cell senescence. NCOA4, a cargo receptor for ferritinophagy, mediates degradation of ferritin and contributes to iron accumulation. Besides, we found that iron overload leads to mitochondrial dysfunction. As a result, mitochondrial DNA (mtDNA) is released from damaged mitochondria to cytoplasm. Cytoplasm mtDNA activates the cGAS-STING pathway and promotes inflammatory senescence-associated secretory phenotype (SASP) and cell senescence. Meanwhile, iron chelator Deferoxamine (DFO) significantly rescues RPE senescence and retinopathy induced by FAC or D-gal in mice. Taken together, these findings imply that iron derived from NCOA4-mediated ferritinophagy causes cellular senescence via the cGAS-STING pathway. Inhibiting iron accumulation may represent a promising therapeutic approach for age-related diseases such as AMD.
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Bin Chen,Hang Li,Hong Zhang,Junyan Xu,Shuofu Liang,Ghazal Shokraneh,Hecheng Ma,Gang Wang,Junhao Lin,Zhijian Wei
Background Diabetic wound, a severe complication of diabetes mellitus, are characterized by chronic inflammation, impaired angiogenesis, and prolonged wound healing. As a somatostatin analog, octreotide (Oct) has been previously found to promote wound healing. However, its application is limited by its low stability and susceptibility to enzymatic degradation. Methods Octreotide was incorporated into a dual-network hydrogel (CS-PBA/PVA/PA) with a 3D porous structure using a one-pot method to form CPP@Oct. Its physicochemical properties, drug release behavior, and biological effects were evaluated in vitro and in vivo. Network pharmacology, Western blotting, immunohistochemistry, and animal models (db/db mice and diabetic rats) were used to investigate the mechanisms and therapeutic effects of CPP@Oct. Results The unique design of the CPP@Oct double-network hydrogel demonstrates exceptional swelling capacity, self-healing properties, and controlled drug release characteristics in high-glucose environments. It significantly reduced inflammatory markers and reactive oxygen species (ROS), promoted angiogenesis (increased CD31, VEGF), and enhanced mitochondrial function. In animal models, CPP@Oct accelerated wound closure, increased collagen deposition, and improved vascular density. Mechanistically, it suppressed the cGAS-STING pathway, alleviating inflammation and promoting tissue repair. Conclusion CPP@Oct hydrogel offers a promising therapeutic strategy for diabetic wound by simultaneously addressing inflammation, angiogenesis, and tissue repair through cGAS-STING pathway inhibition. Its dual-network design provides a versatile platform for targeted drug delivery in wound healing applications.
研究领域:
生物医学工程
·
伤口愈合
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药物递送
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分子生物学
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糖尿病研究
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DOI
高影响因子
ACS Applied Materials & Interfaces
·
2026
·
IF 8.2
Yanfang Cheng,Yebi Qin,Wenhui Zhu,Weirong Yao,Hang Zou,Bairong He,Lizhi Yan,Lei Zheng
Photoimmunotherapy is limited by inadequate dendritic cells (DCs) antigen presentation and cytotoxic T lymphocytes (CTLs) dysfunction. Innate immune activation can potentiate DCs maturation and restore CTLs function, augmenting photoimmunotherapy efficiency. Herein, we developed a biomimetic gold nanorod-core/mesoporous manganese dioxide (MnO2)-shell nanoagonist (denoted as m@AMCR) loaded with chlorin e6 and rapamycin (Rap) to synergize photodynamic therapy (PDT)/photothermal therapy (PTT) with cGAS-STING pathway activation for enhanced tumor treatment. Tumor cell membrane biomimetic camouflage conferred m@AMCR with self-targeting ability toward homologous cancer cells. Subsequently, intratumoral glutathione triggered MnO2 decomposition to release Rap. Rap augmented PDT/PTT by suppressing hypoxia-inducible factor-1α and heat shock protein 70 expression while downregulating matrix metalloproteinase-2 to inhibit tumor metastasis. Concurrently, the released Mn2+ activated the cGAS-STING pathway, promoting DCs maturation and CTLs infiltration. Finally, the combination of photoimmunotherapy-induced immunogenic cell death and cGAS-STING activation potently suppressed primary tumor growth and lung metastases. Overall, this biomimetic self-augmenting nanoagonist established a paradigm for tumor immunotherapy by integrating photoimmunotherapy with cGAS-STING-mediated innate immune activation.
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高影响因子
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