JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Wang Huan-Hui,Nan Long-Yi,Zheng Yan,Guo Jianpeng
Sonodynamic therapy (SDT) offers deep tissue penetration and noninvasive tumor treatment, yet its efficacy remains limited by inadequate reactive oxygen species (ROS) generation and an immunosuppressive tumor microenvironment (TME). In this work, we developed a porphyrin-based bimetallic nanoplatform by integrating Fe and Mn centers within a structurally ordered metal-organic framework (MOF), followed by surface modification with the tumor-homing peptide CRGDK to achieve active targeting. The rationally engineered Mn-Fe(TCPP) MOF exhibits a spatially confined configuration that minimizes π-π aggregation of porphyrins enhancing ROS production under ultrasound (US). Meanwhile, Fe 3+ and Mn 2+ are released in the mildly acidic TME. The Fe 3+ catalyzes Fenton-like reactions to generate abundant •OH radicals, leading to glutathione (GSH) depletion, glutathione peroxidase-4 (GPX4) inhibition, and triggers ferroptosis. Simultaneously, Mn 2+ and ROS inflict mitochondrial damage and cause cytosolic double-stranded DNA (dsDNA) leakage, thereby activating the cGAS-STING signaling pathway and amplifying type I interferon (IFN-I) responses. This dual immunometabolic modulation induces immunogenic cell death (ICD), promotes dendritic cells (DCs) maturation, and strengthens adaptive antitumor immunity. Overall, this study presents a concise strategy coupling ferroptosis induction with innate-immune activation through a porphyrinic bimetallic MOF, offering a promising direction for SDT-based immunotherapy against hard-to-treat tumors. Graphical The alternative text for this image may have been generated using AI.
✓ 已验证
DOI
PubMed
高影响因子
Pharmaceutics
·
2026
·Vol. 18
·期 6
·649
·
IF 6.9
Congyi Zhang,Haotian Wu,Xiaotong Chen,Wenze Yin,Shizhuan Huang,Dixiang Wen,Xueting Song,Xiaoyan Xu,Changmei Zhang,Sheng Tai
Background/Objectives: This study aimed to develop a novel tumor-associated macrophage (TAM)-targeting nanoplatform to improve the solubility and bioavailability of camptothecin (CPT) and achieve active targeted drug delivery for enhanced anti-tumor immunotherapy.Methods: We constructed a sialic acid-disulfide bond-camptothecin (SA-SS-CPT) nanowire system. Sialic acid was used as a targeting ligand to specifically recognize the overexpressed Siglec-E receptor on TAMs. Upon cellular internalization, the disulfide bond was designed to respond to intracellular glutathione (GSH), enabling controlled drug release.Results: The SA-SS-CPT nanowires significantly improved CPT solubility and enabled targeted delivery to TAMs. Following GSH-responsive cleavage and CPT release, the nanowires induced DNA damage in TAMs, activating the cGAS-STING signaling pathway. This promoted TAM polarization toward the M1 phenotype, enhanced pro-inflammatory and anti-tumor immune responses, and inhibited tumor immune escape. Furthermore, SA-SS-CPT synergistically improved the efficacy of PD-L1 blockade immunotherapy, remodeling the tumor immune microenvironment.Conclusions: The SA-SS-CPT nanoplatform effectively targets TAMs, repolarizes them to an anti-tumor M1 phenotype, and activates the cGAS-STING pathway. It shows strong potential for overcoming tumor immune escape and synergizing with PD-L1 checkpoint blockade to achieve significant tumor clearance.
✓ 已验证
DOI
高影响因子
Materials Today Bio
·
2026
·
IF 11
Linhao Jing,Shuaijun Zhao,Chenguang Sun,Fangfang Cui,Yaning Xia,Yupeng Shi,Weijie Wang
Immunotherapy has reshaped cancer treatment, yet its efficacy in many solid tumors remains limited by an immunosuppressive microenvironment and insufficient antigen presentation. As a central gatekeeper of antitumor immunity, the cGAS-STING pathway represents a key axis for converting tumor-intrinsic stress into productive immune priming. Here, we propose an integrated strategy that couples immunogenic tumor cell death with tumor-restricted cGAS-STING activation and adjuvant-amplified innate signaling. Cuproptosis, a recently identified copper-dependent cell-death program, can act as an endogenous trigger of tumor-intrinsic cGAS-STING activation, providing a promising avenue to link cytotoxicity with immune stimulation. We engineered a biomimetic, tumor-responsive nanoplatform (Cu-R837@CM) by co-assembling Cu 2+ with the TLR7 agonist R837 and cloaking the core with homologous tumor cell membranes to enhance tumor targeting and intratumoral retention. In vitro, Cu-R837@CM released Cu 2+ under acidic conditions, inducing glutathione depletion and ROS accumulation, promoting DLAT aggregation and mitochondrial dysfunction, increasing intracellular 2′3′-cGAMP, and activating cGAS-STING signaling. Concurrently, R837 enhanced dendritic-cell maturation and cytokine production, thereby improving antigen presentation. In vivo, Cu-R837@CM markedly inhibited tumor growth, increased CD4 + /CD8 + T-cell infiltration, and remodeled the tumor immune microenvironment toward an antitumor phenotype. Notably, combining Cu-R837@CM with PD-L1 blockade achieved complete tumor regression and significantly prolonged survival. Collectively, Cu-R837@CM offers a clinically translatable nanoadjuvant paradigm that integrates cuproptosis-driven cGAS-STING activation with TLR7 co-stimulation for hepatocellular carcinoma immunotherapy.
✓ 已验证
DOI
PubMed
高影响因子
Nature Metabolism
·
2026
·Vol. 8
·期 8
·1713-1729
·
IF 27.5
Deng Jiangming,Meng Wen,Yang Yuanqin,Xiao Ting,Jin Zhangliu,Wang Jing,Li Qing-xin,Xie Lingxiang,Hu Jingyi,Song Rong,Hu Yibo,Chu Yi,Li Qing,Jin Ping,Wang Zheng,Wu Irene XY,Liu Feng,Xiao Yang
The gut constantly interacts with both pathogens and dietary signals, but how it balances immune and metabolic responses remains unclear. Here we show that intestinal cGAS, a key DNA sensor, acts as a regulator linking gut immunity to whole-body metabolism. We show that cGAS signalling is activated in the intestines of humans and male mice with obesity, leading to increased type I interferon production and heightened immune activity in intestinal cells. Strikingly, deleting cGAS specifically in intestinal epithelial cells enhances energy expenditure, protects against diet-induced obesity and improves metabolic health. These effects depend on the gut microbiota, particularly Lactobacillus murinus and its metabolite indole-3-acetic acid (IAA), which promotes adipose thermogenesis. Our findings position intestinal cGAS as a key driver of obesity through gut-to-fat signalling and suggest that targeting the intestinal cGAS–microbiota IAA axis could offer promising strategies to combat obesity and related metabolic diseases.
✓ 已验证
产品关联
DOI
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Xinying Yu,Bei Li,Jie Yan,Wenxi Li,Hao Tian,Guohao Wang,Songtao Zhou,Yunlu Dai
Proteotoxic stress, caused by the accumulation of abnormal unfolded or misfolded cellular proteins, can efficiently activate inflammatory innate immune response. Initiating the mitochondrial proteotoxic stress might go forward to enable the cytosolic release of intramitochondrial DNA (mtDNA) for the immune-related mtDNA–cGAS–STING activation, which however is easily eliminated by a cell self-protection, i.e., mitophagy. In light of this, a nanoinducer (PCM) is reported to trigger mitophagy-inhibited cuproptotic proteotoxicity. Through a simple metal-phenolic coordination, PCMs reduce the original Cu 2+ with the phenolic group of PEG-polyphenol-chlorin e6 (Ce6) into Cu + . Cu + thereby performs its high binding affinity to dihydrolipoamide S-acetyltransferase (DLAT) and aggregates DLAT for cuproptotic proteotoxic stress and mitochondrial respiratory inhibition. Meanwhile, intracellular oxygen saved from the respiratory failure can be utilized by PCM-conjugated Ce6 to boost the proteotoxic stress. Next, PCM-loaded mitophagy inhibitor (Mdivi-1) protects proteotoxic products from being mitophagy-eliminated, which allows more mtDNA to be released in the cytosol and successfully stimulate the cGAS–STING signaling. In vitro and in vivo studies reveal that PCMs can upregulate the tumor-infiltrated NK cells by 24% and enhance the cytotoxic killing of effector T cells. This study proposes an anti-tumor immunotherapy through mitochondrial proteotoxicity.
研究领域:
癌症生物学
·
免疫学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2026
·
IF 30.6
Jiali Zhu,Lei Wang,Changjie Lin,Shuchen Bian,Xiaohan Luan,Yingying Sui,Luhang Piao,Wen Zhou
TREX1, but not other DEDDh exonucleases, restrains cyclic GMP-AMP synthase- stimulator of interferon genes (cGAS-STING) activation by cytosolic DNA. Here, we examined the mechanisms underlying this specificity. Biochemical comparison of TREX1 and TREX2 mapped TREX1’s ability to degrade dsDNA and suppress cGAS signaling to a single amino acid, R128. Metazoan TREX proteins containing an R128-equivalent functioned as double-stranded DNA (dsDNA) nucleases, often alongside cGAS-like receptors, defining an evolutionarily conserved family. Structurally, TREX1-R128 contacted the non-substrate strand to enable efficient dsDNA binding and cleavage. Examination of conserved structural features of the R128-containing TREX family further identified a substrate-sensing loop that inserted into the active-site cleft and stabilized the substrate strand. In human TREX1, a distinct auxiliary DNA-binding surface (B-site) strengthened DNA engagement and cGAS restraint independent of DNase activity, suggesting a competitive function. Autoimmune-associated TREX1 mutations mapped to TREX1-dsDNA interfaces, and mutations disrupting these interactions increased cGAS-STING signaling and antitumor immunity in murine models. Thus, a modular dsDNA-recognition architecture defines TREX1 specificity and regulation of the cGAS-STING pathway.
✓ 已验证
DOI
PubMed
高影响因子
Nanoscale
·
2025
·
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
·
免疫学
·
纳米医学
✓ 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
·
肝脏病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
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
·
肝脏病学
·
分子生物学
·
免疫学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2026
·
IF 11
Jiajia Jia,Zhitong Guan,Jiaxin Wang,Ting Fang,Jiajun Sun,Aiyang Tong,Yingzhen Fan,Ming Zhao,Dongkai Wang,Zheran Wang,Ji Li
Although cGAS-STING immunotherapy holds immense potential, its efficacy is severely compromised by pathway evasion. To overcome this, we engineered a core-shell bilayer nanobomb (M/ZIF/MnO 2 @DBCO) via a template-assisted approach, integrating MSC1094308 into ZIF-8 cores followed by MnO 2 shell deposition and DBCO functionalization. In a simulated tumor microenvironment, ZIF-8 loading accelerated Mn 2+ release from MnO 2 , increasing the cumulative release by nearly 30% within 8 h compared to pristine MnO 2 . Cellular assays demonstrated rapid bio-orthogonal targeting of azide-modified tumors, achieving lysosomal escape within 6 h postuptake. Subsequently, MnO 2 -mediated glutathione (GSH) depletion and hydroxyl radical (·OH) generation, combined with Zn 2+ induced mitochondrial oxidative stress, produced cytotoxic reactive oxygen species (ROS) that triggered immunogenic cell death. Furthermore, Mn 2+ , Zn 2+ , and dsDNA released from damaged mitochondria cooperatively activated the cGAS-STING pathway. Concurrently, MSC1094308 inhibited ESCRT-mediated negative regulation, as evidenced by a ∼0.2 decrease in the p-STING/VPS4B-RFP colocalization coefficient, confirming the blockade of cGAS-STING evasion. In vivo studies revealed that the nanoplatform profoundly stimulated antitumor immunity, increasing tumor-infiltrating cytotoxic T lymphocytes approximately 8-fold versus untreated controls after 21 days. This work establishes an integrated strategy harnessing Zn 2+ /Mn 2+ synergy, nanobomb reactivity, and ESCRT inhibition to circumvent cGAS-STING evasion, offering a promising paradigm for cancer immunotherapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Chao Wang,Chenxuan Zhao,Yesong Yao,Zhiwen Zou,Anxin Shi,Zhuo Feng,Mingkang Yang,Yue Yu,Yang Liu,Xuehui Rui,Jinhui Wu
Intracellular nucleotide imbalance between ribonucleotides and deoxyribonucleotides can trigger cytosolic mitochondrial DNA (mtDNA) release and subsequent activation of the cGAS–STING pathway. However, fluoropyrimidine-induced nucleotide imbalance is constrained by their metabolic instability. Here, we leverage ribonucleotides to amplify floxuridine (FUDR)-induced mtDNA release and cGAS–STING activation for enhanced cancer chemoimmunotherapy. We identified that cytidine monophosphate (CMP) significantly enhances FUDR-mediated activation of the mtDNA-driven cGAS–STING pathway, inducing over 300-fold upregulation of the interferon gene Ifnb1 and initiating STING-dependent antitumor immunity. Genome-wide CRISPR-Cas9 screening identified five pyrimidine-metabolizing enzymes (CMPK1, CMPK2, TYMP, UPP1, and UPP2) that are responsible for the metabolic instability of floxuridine monophosphate (FdUMP). CMP and its intracellular metabolites can metabolically block these enzymes, thereby increasing the peak intracellular concentration of FdUMP by over 500-fold and extending its half-life by more than 20-fold, which in turn promotes sustained intracellular nucleotide imbalance. To translate this mechanism into therapy, we co-encapsulated FdUMP and CMP into hybrid lipid nanoparticles (FC-NPs). FC-NPs robustly activated STING-dependent antitumor immunity, achieving remarkable therapeutic efficacy in multiple murine colorectal cancer (CRC) models. Our study not only addresses the long-standing issue of fluoropyrimidine metabolic instability but also reveals a novel ribonucleotide-mediated immunomodulatory mechanism, providing a promising strategy to potentiate chemoimmunotherapy in CRC.
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）