JOURNAL OF NANOBIOTECHNOLOGY
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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.
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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.
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高影响因子
Materials Today Bio
·
2026
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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.
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高影响因子
ACS Applied Materials & Interfaces
·
2026
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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
Pharmaceutics
·
2026
·Vol. 18
·期 6
·649
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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.
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CHEMICAL ENGINEERING JOURNAL
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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
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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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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
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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
·
分子生物学
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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.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Qingqing Huang,Nana Feng,Xianghui Cao,Jian Xiao,Qiushi Li,Biyu Zhou,Yating Bai,Yu Zhao,Zhanzhan Zhang,Yang Liu
Breast cancer generally does not respond to immunotherapy due to its inherently low immunogenicity and insufficient coordination between innate and adaptive immune responses. Here, we demonstrated that concurrent activation of immunogenic cell death (ICD) and the cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) pathway synergistically amplifies antitumor immunity by promoting dendritic cell maturation, co-stimulatory signaling, and T cell priming. Building on these mechanistic insights, we designed a nanoparticle-based immunomodulator (nanoIM) that integrates a serum albumin-metal core with an endoplasmic reticulum (ER)-targeting polymer shell. Within the tumor microenvironment (TME), nanoIM induces ER stress-mediated ICD and simultaneously releases Mn 2+ or Zn 2+ ions to activate the cGAS–STING pathway, thereby bridging innate and adaptive immune activation. Systemic administration of nanoIM in breast cancer-bearing mice elicited potent T cell infiltration, robust tumor regression, prolonged survival, and effective prevention of metastasis and recurrence. This study uncovers the molecular crosstalk between ICD and cGAS–STING signaling and establishes a nanomaterial-based strategy for durable and systemic immune activation in breast cancer immunotherapy.
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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.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Manqing Zhang,Yufei Lan,Qu Yue,Jinjun He,Lei Li,Huan Zhang,Yaoyuan Dong,Yuankai Wang,Jiankun Lu,Zhijie Lu,Feiyunduo Hao,Sui Chen,Yixiao Jiang,Chao Zhang,Yan Zhao,Hongbo Guo
Alzheimer's disease (AD) pathological progression is intimately linked to microglial inflammatory activation mediated by the cGAS-STING pathway. Small interfering RNA targeting STING (siSTING) is a precise therapeutic to silence STING and interfere with this pathway, but its clinical translation is severely limited by serum nuclease degradation, inadequate blood-brain barrier (BBB) penetration, and suboptimal targeting. We constructed a lock-equipped six-helix DNA bundle for siSTING delivery. Prior to reaching AD lesions, siSTING was efficiently sequestered within the DNA bundle, ensuring its structural integrity; upon arrival at the lesion site, the carrier undergoes a conformational change in response to the high expression of CD64, thereby triggering the controlled release of encapsulated siSTING. Functional assessments showed this system significantly suppressed cGAS-STING activation, reduced cerebral Aβ plaque deposition, and promoted microglial polarization from M1 (proinflammatory) to M2 (anti-inflammatory). These effects ameliorated memory and learning deficits in AD model mice via enhanced neuroprotection, offering a novel platform for precise targeted therapy of AD.
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高影响因子
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