Advanced Science
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2026
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IF 14.1
Shuang Liang,Yiwei Tian,Feiyu Zhao,Yue Han,Kongshuo Ma,Linna Hai,Kaiqing Yun,Yueyang Zhao,Siqi Zhang,Ziyi Zhang,Yuxuan Peng,Kuan Hu,Jing Zhong,Bai Xiang,Zhaohui Wang
The cGAS-STING pathway, a critical cytosolic DNA-sensing mechanism in innate immunity, holds significant promise for cancer immunotherapy. However, conventional DNA-damaging therapies lack tumor specificity and cause damage to normal tissue. Furthermore, dendritic cells (DCs), central to the STING-mediated immune response, exhibit extrinsic immunosuppression via inhibitory receptors such as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), which impairs DNA internalization and subsequent pathway activation. Herein, we engineered a telomere stress-induced nanoreactor composed of a pH-responsive zeolitic imidazolate framework-8 encapsulating telomerase-targeted 6-thio-2’-deoxyguanosine (6-thio-dG), with TIM-3 antibodies (αTIM-3) adsorbed onto its surface. Following accumulation in the tumor, the nanoreactor degrades within the acidic tumor microenvironment, releasing 6-thio-dG to induce tumor cell-specific telomeric DNA damage. Concurrently, the αTIM-3 blocks TIM-3 receptors on DCs, thereby enhancing their internalization of the released DNA. This dual-action strategy drives robust cGAS-STING activation, enhancing type I interferon production and DCs maturation. In murine models of immunogenic and poorly immunogenic tumors, the nanoreactor significantly suppresses tumor growth and prolongs survival. By coupling tumor-intrinsic telomere stress with DC-extrinsic checkpoint inhibition, this work establishes a precision platform for cGAS-STING pathway activation, presenting a promising therapeutic strategy for telomerase-positive malignancies.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Tongtong Wu,Qiwen Yu,Yun Wang,Hongwei Tang,Wenzhi Guo
Background Liver ischemia/reperfusion (I/R) injury is an unavoidable complication during liver surgery, particularly in liver transplantation. Trillin exhibits anti-inflammatory, antioxidant, anti-apoptotic, and autophagy-inhibitory effects. However, Trillin has not been studied in liver I/R injury. Methods In this study, we investigated the effects of Trillin in liver I/R and AML12 hypoxia/reoxygenation (H/R) models. We assessed Trillin's impact on inflammatory responses, oxidative stress, apoptosis, and autophagy through H&E staining, serum transaminase levels (ALT, AST), cell viability assays, propidium iodide (PI) staining, MitoSOX staining, immunohistochemistry (IHC), transmission electron microscopy (TEM). Qualitative and quantitative analyses of mRNA and protein levels were performed to evaluate inflammatory cytokines, autophagy-related proteins, and the cyclic GMP-AMP synthase (cGAS) – stimulator of interferon genes (STING) pathway. Molecular docking and dynamics simulations were conducted to validate the binding and stability between Trillin and cGAS. Results Our results demonstrate that Trillin alleviates liver ischemia-reperfusion injury through the attenuation of autophagy in both in vitro and in vivo models. Additionally, Trillin could bind to cGAS and inhibit the activation of the cGAS-STING pathway. cGAS overexpression significantly reversed Trillin's protective effects in liver I/R injury and its inhibitory effects on the cGAS-STING pathway. Conclusion Trillin exerts protective effects against liver I/R injury by inhibiting the cGAS-STING pathway.
研究领域:
药理学
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肝脏病学
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分子生物学
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免疫学
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细胞生物学
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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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
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药理学
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免疫学
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Materials Today Bio
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2025
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IF 10.2
Yong Fan,Zexuan Niu,Li Yin,Longtao Yao,Sheyuan Ding,Yu Tong,Jiao Wang,Zheping Hong,Jihang Chen,Qiong Zhang,Lichen Ji,Jiaxin Chen,Chen Xia,Qing Bi
Osteoarthritis (OA) is a progressive degenerative disorder which severely threatens the quality of life of older individuals. OA progression is closely related to heightened levels of mitochondrial reactive oxygen species (mtROS). Although nanozymes have a good ROS-scavenging effect, they cannot precisely scavenge mtROS because of the immune rejection of cell membranes, lysosomal escape, and the inability of conventional nanozymes to directly target mitochondria. Dual-target nanozymes were engineered to precisely scavenge mtROS in chondrocytes. We used chondrocyte membrane-camouflaged TPP-modified hollow Prussian blue nanozymes and subsequently encapsulated these nanozymes in a hybrid glycyrrhizic acid hydrogel. The therapeutic efficacy and underlying mechanisms were assessed in vitro and in vivo. The novel nanozymes enhanced cell selectivity, immune evasion capabilities, and mitochondrial targeting. The dual-targeted nanozymes exerted a pronounced therapeutic impact on inflammatory chondrocytes, mitigated mtDNA leakage by precisely scavenging mtROS, dampened cGAS-STING-NF-κB signaling, and enhanced chondrocyte function. The hybrid hydrogels also exhibited improved therapeutic outcomes. We confirmed the beneficial effects of the nanozyme-hydrogel combination on OA progression in mice. The nanozyme-hydrogel combination can reduce precisely scavenge mtROS in chondrocytes, avoiding the leakage of mtDNA and suppressing the cGAS-STING-NF-κB signaling pathway, thereby decreasing inflammatory responses and alleviate OA progression.
研究领域:
医学
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生物材料学
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分子生物学
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Advanced Science
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2024
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IF 14.3
Zhen Tong,Jia-Peng Zou,Su-Yun Wang,Wei-Wei Luo,Yan-Yi Wang
Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (β) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-β and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-β and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-β- or IFN-γ-mediated antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.
研究领域:
免疫学
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分子生物学
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微生物学
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癌症研究
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高影响因子
CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Yahui Wu,Zhipu Liu,Yi Zhang,Senfeng Zhao,Miaoqing Li,Ruiyang Zhang,Jiahui Cao,Peng Liu,Liming Song,Yin Liu,Yunpeng Zhai,Weijie Wang,Ruopeng Liang,Rongtao Zhu,Yupeng Shi,Yuling Sun
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Photoimmunotherapy, which integrates photodynamic/photothermal therapy with immunomodulation, has emerged as a promising therapeutic strategy. However, its efficacy is often constrained by the immunosuppressive tumor microenvironment (TME) characteristic. Activation of the cGAS/STING signaling pathway represents a key mechanism for initiating innate immunity, thereby providing an attractive target for enhancing immunotherapy. In this study, we identified acetaminophen (APAP) as a potent in situ STING pathway activator capable of activating the cGAS/STING pathway and inducing apoptosis in HCC cells. To enable tumor-targeted delivery of APAP, we constructed a degradable nanoplatform termed GSST/APAP@HA. This system was fabricated by incorporating disulfide bonds into a Gd-TCPP-based amorphous metal-organic framework (MOF)-like networks (Gd-aMOF), loading it with APAP, and modifying the surface with hyaluronic acid (HA) for active targeting. Both in vitro and in vivo evaluations demonstrated efficient tumor accumulation of the nanoplatform and photodynamic-triggered immunogenic cell death (ICD), which provoked a robust antitumor immune response. Simultaneously, laser-induced reactive oxygen species (ROS) within the acidic TME promoted Gd-aMOF degradation and APAP release, leading to cGAS/STING pathway activation and remodeling of the immunosuppressive microenvironment. This combinatory approach resulted in significant tumor suppression in mouse HCC models. Coupled with its low cytotoxicity, excellent biocompatibility and superior magnetic resonance imaging (MRI) capability, the GSST/APAP@HA nanoplatform represents a promising theranostic strategy for cancer photoimmunotherapy.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Tu Maopu,Deng Xiaoyu,Zhou Zhiyong,Li Xiaodong,Mao Shengxun,Lai Bin,Pang Lisong,Zhong Qilin,Cao Jiaqing,Liu Haipeng,Ouyang Xi
Microsatellite-stable (MSS) colorectal cancer (CRC) resists immunotherapy due to its immunosuppressive tumor microenvironment (TME). The cGAS-STING pathway, a key regulator of innate immunity, offers a promising strategy to overcome the immunotherapy resistance in CRC. However, its limited endogenous activation, coupled with the immunosuppression driven by lactate accumulation, significantly compromises the efficacy of standalone STING activation. In response, we developed a multifunctional copper-based metal-organic framework (Cu-MOF) nanoparticle co-loaded with the STING agonist SR-717 and the glycolysis inhibitor 3-bromopyruvate (3-BP), coated with tumor cell membranes (termed BR@CuM@CM), to achieve integrated metabolic modulation and immune activation. BR@CuM@CM nanoparticle achieves tumor-specific accumulation via homotypic targeting and undergo glutathione-responsive degradation to trigger drug release. The released SR-717 activates the STING pathway, promoting dendritic cell (DC) maturation and thereby enhancing cytotoxic T-cell recruitment. Concurrently, Cu²⁺ triggers Fenton-like reactions to generate reactive oxygen species (ROS), inducing mitochondrial DNA release and further amplifying STING signaling. Meanwhile, 3-BP suppresses lactate production by inhibiting glycolysis, which not only repolarizes M2-type tumor-associated macrophages toward the M1 phenotypes and suppresses regulatory T cell (Treg) infiltration, but also alleviates cGAS lactylation to enhance cGAS activity and amplifying STING-mediated immune responses. When combined with anti-PD-1, the nanoparticle significantly inhibits tumor growth and liver metastasis. Collectively, BR@CuM@CM synergistically modulates metabolism and immune signaling to convert immunologically “cold” tumors into “hot” tumors, demonstrating translational potential to overcome immunotherapy resistance in CRC. Graphical
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CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Shichao Zhang,Quan Liao,Qidan Tan,Yuhan Xie,Tengfei Li,Zhouting Tuo,Rui Yao,Yuanjiong Qi,Shiyong Qi
A biomimetic ultrasmall cerium–polyphenol nanoplatform (CeSAB) is developed for precision therapy of acute kidney injury. • CeSAB enables efficient renal targeting and mitochondrial accumulation via albumin-mimicking surface engineering. • The nanoplatform modulates redox homeostasis and suppresses cGAS–STING–mediated inflammatory signaling. • CeSAB disrupts mitochondrial ROS-driven pathological cascades in AKI. • Significant renal protection with excellent biosafety and in vivo clearance is achieved in multiple AKI models. Acute kidney injury (AKI) remains a major clinical challenge due to the absence of effective therapeutic interventions. Mitochondrial dysfunction in proximal tubular epithelial cells (PTECs) induces excessive reactive oxygen species (ROS) accumulation, leading to mitochondrial DNA (mtDNA) release and activation of the cGAS–STING inflammatory pathway, thereby establishing a self-amplifying cycle of oxidative stress and inflammation. Herein, we develop a biomimetic ultrasmall cerium–polyphenol nanoplatform (CeSAB) to precisely disrupt this pathogenic cascade. CeSAB is constructed through coordination-driven assembly of Ce 3+ and salvianolic acid B (SAB), integrating polyphenol-derived antioxidant activity with the dynamic redox-buffering capability of cerium. Bovine serum albumin (BSA) functionalization endows CeSAB with albumin-mimetic renal-selective delivery through megalin-mediated uptake, enabling efficient mitochondrial localization. Upon mitochondrial accumulation, CeSAB restores redox homeostasis, preserves mitochondrial integrity, and prevents mtDNA release through SAB-mediated antioxidant activity, thereby suppressing cGAS–STING activation and downstream inflammatory responses. The Ce 3+ /Ce 4+ redox cycle further reinforces oxidative microenvironment regulation, while the pH-responsive coordination structure facilitates acid inflammatory microenvironment-triggered drug release, thereby alleviating oxidative stress and tissue hypoxia. In multiple AKI models, CeSAB significantly ameliorates renal dysfunction, oxidative injury, and inflammation with excellent biosafety. This work establishes a biomimetic mitochondria-targeted nanoplatform for interrupting ROS-driven inflammatory amplification, providing a promising approach for precision treatment of AKI. Download: Download high-res image (123KB) Download: Download full-size image
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Materials Today Bio
·
2025
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IF 10.2
Jia Li,Yangbo Xu,Congrui Zhao,Xiaoyu Chen,Chuchu Xu,Chuan Zhou,Hui Wang,Antian Xu,Fuming He
The innate immune response to bone biomaterials critically regulates osteogenesis, yet the molecular mechanisms governing neutrophil-macrophage crosstalk remain poorly understood. Building on our discovery of neutrophil involvement in bone regeneration, we investigated the E3 ubiquitin ligase-Tripartite motif containing protein 30a(TRIM30a) as a potential orchestrator of inflammatory resolution and osseointegration. Through integrated multi-omics analysis of pro-osteogenic versus non-osteogenic metallic implants, we identified TRIM30a as a key regulator. Using conditional knockout mice (whole-body, neutrophil-specific, and macrophage-specific TRIM30a deficiency) combined with NETosis assays and inflammatory signaling profiling, we systematically evaluated TRIM30a's role on NETosis/cGAS-STING axis in bone regeneration, with pharmacological validation using DNase I in murine femoral implant models. TRIM30a expression is positively correlated with the osteogenic ability of pro-osteogenic implants. Mechanistically, TRIM30a suppressed NF-κB/NLRP3 in neutrophils, while synergizing with NET-derived dsDNA to modulate cGAS-STING signaling in macrophages, achieving balanced cytokine production. Therapeutic intervention with DNase I rescued bone formation in TRIM30a-deficient mice, confirming the pathway's clinical relevance. Our work establishes TRIM30a as a master regulator of bone regeneration through dual mechanisms: restraining neutrophil hyperactivation via NF-κB/NLRP3 inhibition while cooperating with dsDNA to calibrate macrophage cGAS-STING signaling, revealing a targetable immunomodulatory axis for enhancing osseointegration. These findings provide new insights into the immune-bone regeneration interface and suggest novel therapeutic strategies for implant-related bone repair.
研究领域:
免疫学
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骨再生医学
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生物材料科学
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分子生物学
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炎症研究
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Haiqin Song,Nicolás Montesdeoca,Elizaveta Efanova,Xuan Li,Johannes Karges,Haihua Xiao,Kun Shang,Hanchen Zhang
Immunotherapy has had a tremendous impact on cancer treatments. Although frequently used inside the clinics, the application of immunomodulating compounds remains restricted due to the immunosuppressive tumor microenvironment. Among the promising methods, the activation of the stimulator of interferon genes (STING) pathway has emerged as a next-generation immunotherapeutic target. Despite promising preliminary results, the application of STING activating agents is strongly limited due to poor tumor selectivity and poor bioavailability. To overcome these limitations, herein, the first example of a cobalt(III) cyclam prodrug capable of inducing a chemotherapeutic effect and activating the STING pathway is reported. The cobalt(III) complex was found to be stable under physiological conditions, but released its axial ligands within the reducing cancerous microenvironment. While the reduced metal complex triggered a strong cytotoxic response by chemotherapy, the released organic ligands induced a strong immune response using the STING pathway, resulting in a multimodal treatment. To further enhance the pharmacological properties and provide tumor selectivity, the metal complex was encapsulated in polymeric nanoparticles. Upon injection into the blood stream, the nanoparticles accumulated in the triple-negative breast cancer tumor of the mouse model, activated the immune response inside the animal, and caused a nearly complete eradication of the tumor.
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ADVANCED FUNCTIONAL MATERIALS
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2026
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IF 19.9
Liping Bai,Xinyue Wu,Xiaorong Kou,Miaomiao Zhang,Xinchao Li,Ning Wang,Xue Wu,Qinjie Wu,Changyang Gong
The cGAS-STING pathway is an essential element of antitumor immunity. However, its activation triggers immunosuppressive molecules like PD-L1 to feedback upregulate, which limits therapeutic efficacy. Herein, we develop a programmable tumor-activated nanoCRISPR platform (PATROL) that co-delivers CRISPR/Cas13a-CARM1 plasmid and PD-L1 blocking peptide to stimulate the cGAS-STING-IFN-I pathway and diminish its immunosuppressive feedback loop, thereby improving antitumor efficacy. PATROL achieves enhanced circulation longevity, tumor-targeting specificity, and tissue penetration due to surface modifications such as PEGylation, hyaluronic acid, and TAT peptide. At the same time, its PD-L1 blocking peptide on the surface facilitates drug accumulation with the tumor and inhibits PD-L1 activity. Following exposure to tumor-associated hyaluronidase, PATROL undergoes enzyme-triggered disassembly, surface charge reversal, rapid lysosomal escape, and significant CARM1 knockdown, leading to enhanced cGAS-STING signaling. This bifunctional approach cooperatively reprograms the immunosuppressive tumor microenvironment, increases cytotoxic T lymphocyte infiltration, and elicits powerful antitumor immunity by simultaneously blocking PD-1/PD-L1 signaling and activating the cGAS-STING-IFN-I pathway. PATROL exhibits significant antitumor efficacy in B16-F10 melanoma models, successfully inhibiting tumor growth and prolonging survival. As consequently, PATROL presents an innovative therapeutic strategy that achieves effective tumor suppression by enhancing antitumor immunity through dual-pathway activation.
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PHYTOTHERAPY RESEARCH
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2024
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IF 6.1
Liu-Gen Li,Jun Hu,Ning Han,Nan-Nan Chen,Ting-Ting Yu,Tao Ren,Hua-Zhen Xu,Xing-Chun Peng,Xian-Yu Li,Tian-Qi Ma,Hao Chen,Lei Zhang,Xiao Chen,Mei-Fang Wang,Tong-Fei Li
Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy.
研究领域:
肿瘤学
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免疫学
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药理学
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细胞生物学
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