International Journal of Nanomedicine
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2023
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IF 8
Boyi Yu,Xuanyi Lu,Xianglong Feng,Ting Zhao,Jiaxin Li,Yudie Lu,Fei Ye,Xiongxiong Liu,Xiaogang Zheng,Zheyu Shen,Xiaodong Jin,Weiqiang Chen,Qiang Li
Introduction Radiotherapy is a widely recognized first-line clinical treatment for cancer, but its efficacy may be impeded by the radioresistance of advanced tumors. It is urgent to improve the sensitivity of radioresistant tumors to radiotherapy. In this work, gadolinium oxide nanocrystals (GONs) were utilized as radiosensitizers to enhance the killing effect and reinforce the immune activation of X-ray irradiation on 4T1 breast cancer cells in vitro and in vivo.Methods 1.0 T small animal MR imaging (MRI) system was employed to trace GONs in vivo, while 225 kVp X-ray irradiation equipment was utilized for investigating the radiosensitization of GONs in 4T1 breast cancer cells in vitro and in vivo. Western blot, quantitative real-time PCR (RT-qPCR), immunohistochemistry, immunofluorescence, clonal survival assay, flow cytometry and reactive oxygen species assay were used to explore the biological mechanism of GON sensitization.Results GONs exhibited exceptional utility as contrast agents for both in vivo and in vitro MRI imaging. Interestingly, a single dose of 8.0 Gy X-rays together with GONs failed to confer superior therapeutic effects in tumor-bearing mice, while only 3.0 Gy × 3 fractions X-rays combined with GONs exhibited effective tumor growth inhibition. Moreover, fractionated X-ray irradiation with GONs demonstrated a superior capacity to activate the cGAS-STING pathway.Discussion Fractionated X-ray irradiation in the presence of GONs has demonstrated the most significant activation of the anti-tumor immune response by boosting the cGAS-STING pathway.
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高影响因子
Materials Today
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2025
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IF 22
Ying-Tao Zhong,Zi-Wen Qiu,Ke-Yan Zhang,Zhen-Ming Lu,Zhuo-Feng Li,Jun-Mei Nie,Yi Cen,Hong Cheng,Shi-Ying Li,Xiaoyuan Chen
Pyroptosis-inducing chemotherapeutics hold promise for activating both adaptive and innate immunity in breast cancer immunotherapy. However, their practical efficacy is often limited by inadequate expression of pyroptosis-executed gasdermin and insufficient transfer of tumor-derived DNA. In this work, our findings indicated that the epigenetic drug of decitabine (DEC) can increase the gasdermin E (GSDME) level in breast cancer cells, while the DNA-damaging chemotherapeutic drug of 7-ethyl-10-hydroxycamptothecin (SN38) can activate caspase-3 and cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway. Based on these discoveries, a glutathione (GSH)-responsive nanoplatform equipped with PD-L1 blockade peptide (PD-L1 pep) is further fabricated for targeting delivery of these chemotherapeutic combination to breast cancer cells. Interestingly, the apoptosis-pyroptosis switch (denoted as PL@SD) not only enables the cascade activation of caspase-3 and GSDME to induce an apoptosis-pyroptosis transition, but also accelerates the release of tumor-derived DNA through the pore-formation to elicit the cGAS-STING activity. Concurrently, PL@SD elevates dendritic cell maturation, cytotoxic T lymphocyte infiltration, natural killer cell recruitment and long-term immunological memory effect to boost adaptive and innate immunity, thus synergistically suppressing primary breast cancer, distant lung metastases and tumor rechallenge. Overall, this study presents an elaborate strategy for apoptosis-pyroptosis transition and cGAS-STING activation, which might provide a new insight to expand the applications of the existing therapeutic drugs for tumor immunotherapy.
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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分子生物学
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Communications Biology
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2025
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IF 5.1
Wang Shanshan,Wu Zankai,Song Wenqin,Zhang Hui,Bu Xueshan,Gao Wenwei,Wu Kefan,Xia Zhongyuan,Zhao Bo,Wang Wei
Activation of the cGAS-STING pathway has been proposed as a potential pathogenic mechanism underlying postoperative cognitive dysfuncton (POCD). Analysis of public transcriptomic data from the hippocampus of male mice suggests upregulation of Rbm47 in an experimental POCD model. In vitro, knockdown (KD) of Rbm47 in BV2 cells reduces levels of cGAS, STING, TNF-α, IL-6, and IFN-β under isoflurane and lipopolysaccharide (Iso + LPS) conditions. HT22 cells exposed to culture medium from Rbm47 -KD BV2 cells treated with Iso + LPS show increased levels of MEF2C, GPX4, GSH, and SOD, and reduced levels of MDA and iron. Microglial Rbm47 overexpression amplifies cGAS-STING signaling and aggravates neuronal ferroptosis, which is reversed by the cGAS inhibitor RU.521. Rbm47 KD combined with RU.521 treatment synergistically ameliorates POCD in male mice. Mechanistically, the RRM2 domain of RBM47 interacts with the 3’UTR of cGAS mRNA, enhancing its stability. RUNX1 directly binds to the Rbm47 promoter and facilitates its transcription. RUNX1 overexpression activates the RBM47-cGAS-STING axis and exacerbates neuronal ferroptosis. Conversely, RUNX1 ablation ameliorates POCD, dampens the cGAS-STING signaling, and inhibits ferroptosis, which is abolished by RBM47 depletion. Our findings suggest that repression of RUNX1/RBM47 may represent a promising therapeutic strategy for POCD.
研究领域:
神经科学
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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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麻醉与围术期医学
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高影响因子
International Journal of Biological Sciences
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2026
·Vol. 22
·期 7
·3886-3908
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IF 11.7
Cai Yuchen,Zhou Tianyi,Sun Jiaming,Cai Xueyao,Shi Wenjun,Chen Junzhao,Zouboulis Christos C.,Sun Hao,Fu Yao,Chen Liangbo
Dysregulated lipid metabolism and chronic inflammation are hallmarks of aging, yet their interplay in age-related tissue disorders remains poorly defined. In the ocular surface, age-related meibomian gland dysfunction (ARMGD) is highly prevalent but mechanistically unclear, leading to significant visual impairment without targeted therapies. To identify key molecular drivers of ARMGD, we performed integrated multi-omics screening of aging mouse meibomian glands (MGs) and identified DHCR24, a key cholesterol metabolism enzyme, as a critical regulator of gland homeostasis. Single-cell sequencing identified age-associated downregulation of Dhcr24 predominantly in meibocytes. Based on this finding, we generated a meibocyte-specific Dhcr24 knockout (cKO) model, which exhibited typical ARMGD pathology including glandular atrophy, disrupted lipid homeostasis, and inflammatory activation. Further in vitro studies using SZ95 sebocytes demonstrated that DHCR24 deficiency induces mitochondrial dysfunction and cytosolic mitochondrial DNA (mtDNA) leakage, triggering cGAS/STING-dependent inflammatory senescence. Notably, AAV-mediated restoration of DHCR24 in mice reversed age-related gland pathology. Our findings establish DHCR24 as a dual-target regulator that maintains cholesterol metabolic homeostasis while suppressing mtDNA-driven inflammation via the cGAS-STING pathway, highlighting its therapeutic potential for ARMGD and related disorders characterized by lipid-inflammatory imbalance.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
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IF 5.4
Tao Jiang,Feikai Zhu,Xintao Gao,Xiaochen Wu,Wenyong Zhu,Chuanlong Guo
Acute kidney injury (AKI) is a common clinical problem with no effective treatment. Excessive folic acid (FA) induced kidney tubular injury is characterized by oxidative stress and inflammation, and is a common model of AKI. The excellent pharmacological activity of naringenin (NAR) makes it a potential agent for treating AKI, but its poor solubility limits its application. This study prepared NAR loaded nanoparticles (FU/PVP-NAR) using fucoidan (FU) and polyvinylpyrrolidone (PVP) as carriers, with a particle size of 23.96 ± 2.77 nm. In vitro studies showed that FU/PVP-NAR inhibited excessive FA induced proliferation inhibition, accumulation of reactive oxygen species (ROS), and disruption of mitochondrial membrane potential (MMP) of HK-2 cells. Further confirmed that FU/PVP-NAR inhibited FA induced DNA damage and Cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) activation. In vivo studies showed that excessive FA induced AKI features in mice, such as elevated serum creatinine (SCr) and blood urea nitrogen (BUN) levels, accompanied by pathological damage to kidney tissues. The above AKI characteristics induced by FA were alleviated by FU/PVP-NAR. FU/PVP-NAR also inhibited the decrease in antioxidant enzyme levels in kidney tissues induced by FA. Furthermore, in vivo mechanism studies indicated that FU/PVP-NAR inhibited the release of inflammatory factors by inhibiting DNA damage-cGAS-STING pathway. In summary, this study provided the possibility for FU/PVP-NAR as a potential candidate drug for treating FA induced AKI.
研究领域:
药理学
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肾脏病学
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纳米医学
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高影响因子
Advanced Healthcare Materials
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2023
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IF 10
Yechun Jiang,Yu Jin,Chengcheng Feng,Yayun Wu,Weinan Zhang,Liang Xiao,Zhaoyou Chu,Benjin Chen,Yan Ma,Haisheng Qian,Lingling Xu
Topical therapy has received worldwide attention for in situ tumors owing to its higher efficacy of drug delivery. Herein, this work reports a dissolvable multifunctional hyaluronic acid microneedles (HMNs) patch coloaded with temozolomide (TMZ) and MnCl 2 (TMZ/MnCl 2 @HMN) for chemoimmunotherapy of melanoma. HMNs can ensure the stability of TMZ over time, and exhibit fewer side effects with a localized release way. In particular, TMZ not only promotes dendritic cell maturation by triggering immunogenic cell death in tumor cells, but also induces DNA damage that can further enhance the Mn 2+ -activated cGAS-STING (stimulator of interferon genes pathway). As a result, the TMZ/MnCl 2 @HMN multifunctional platform significantly inhibits lung metastases for melanoma, providing a practical strategy for precision therapy of melanoma.
研究领域:
药学
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肿瘤学
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生物医学工程
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免疫疗法
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PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2025
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IF 7.3
Ziyan Wang,Wei Zhang,Ziyan Liu,Danyang Huang,Huiwen Kang,Jingyu Wang,Guangyu Jiang,Ai Gao
BDE-209 has a causal relationship with adverse health outcomes. However, research on its effect on bone homeostasis is relatively lacking. This study examined the relationship between BDE-209 exposure and bone health, as well as the underlying mechanisms, using both in vitro and in vivo models. In animal studies, female SD rats were administered BDE-209 for 60 days. Bone mineral density, bone microstructure, gut microbiota, and inflammaging markers were measured. Furtherly, THP-1 cell-derived macrophages were treated with a culture medium containing population-relevant dose of BDE-209 or sodium butyrate. The expression of M1 macrophage markers, osteoclast markers, and inflammatory cytokines was measured. Then macrophages were induced by osteoclast conditioned medium to evaluate the effect of BDE-209 on their differentiation into osteoclasts. Results showed reduced humeral bone density, enhanced osteoclast activity, upregulation of IL-1β, TNF-α, IL-6, and activation of PGC-1α/NAD + /cGAS-STING in the exposed group. 16s sequencing revealed that BDE-209 disrupts the abundance of the gut microbiota, notably a reduction in Lachnospiraceae . In vitro, BDE-209 can stimulate macrophages to differentiate more osteoclasts and activate the cGAS-STING pathway, while sodium butyrate can inhibit these effects. This study reveals that gut microbiota dysbiosis is involved in BDE-209-induced bone homeostasis disorder through inflammatory aging and sodium butyrate can mitigate this effect. Overall, this study provides research data for the precaution and treatment of osteoporosis associated with BDE-209 exposure.
研究领域:
毒理学
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免疫学
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骨生物学
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微生物学
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药理学
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高影响因子
ADVANCED MATERIALS
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2026
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IF 29.1
Shi Chen,Mengjia Shi,Yi Chen,Yong Wang,Yi Li,Dayong Yang,Jinhong Guo,Cuiping Mao
Triple-negative breast cancer (TNBC) is associated with poor prognosis due to its highly heterogeneous tumor immune microenvironment and the lack of actionable molecular targets, which collectively limit the efficacy of current therapies. To address these challenges, PEI/siENPP1@Mn-ZIF-8 (PEMZ) is reported, an integrated gene–chemodynamic–immune nanocomplex that activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway through a previously unattainable triple-activation mechanism. PEMZ efficiently encapsulates siENPP1, protects it from degradation, and enables acid-responsive cytosolic release, resulting in sustained ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) silencing and accumulation of tumor-derived cyclic 2′,3′-GMP-AMP (cGAMP). Simultaneously, the Mn 2+ /Zn 2+ ions released from the trienzyme-mimetic nanocomplex, which exhibits peroxidase-, catalase-, and glutathione peroxidase-like activities, amplify intracellular reactive oxygen species, deplete glutathione, and trigger mitochondrial dysfunction. This coordinated redox disruption induces immunogenic cell death and further enhances STING signaling. In vitro and in vivo studies demonstrate that PEMZ markedly suppresses TNBC proliferation and metastasis, promotes dendritic cell maturation, and increases intratumoral CD8 + T-cell infiltration, achieving potent tumor inhibition with minimal systemic toxicity. This work establishes PEMZ as a mechanistically integrated nano-immunotherapy platform, offering a promising and broadly applicable strategy for the precision treatment of TNBC and other ENPP1-overexpressing cancers.
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高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Zhihao Xiao,Jing Jin,Xiangxing Long,Xu Zhu,Jian Jiao,Weirui Kong,Jiangzhu Li,Yuqing Zhuang,Qian Liu,Aihua Gu
This study aimed to investigate the molecular mechanism by which nickel chloride (NiCl₂) exposure promotes the progression of aortic dissection (AD), with a focus on the role of vascular smooth muscle cells (VSMCs). Through a combination of in vivo experiments using β-aminopropionitrile (BAPN)-induced AD mouse models and in vitro experiments on VSMCs, the results demonstrated that NiCl₂ exposure significantly increased the incidence of AD, enlarged the aortic diameter, and exacerbated elastic fiber damage in the aortic wall. Moreover, NiCl₂ could directly bind to the voltage-dependent anion channel 1 (VDAC1) protein on the mitochondria of VSMCs and promote its oligomerization, leading to the leakage of mitochondrial DNA (mtDNA). The leaked mtDNA activated the cGAS-STING signaling pathway in the cytoplasm, thereby inducing the phenotypic transition of VSMCs from a contractile to a synthetic state, enhancing the release of matrix metalloproteinases (MMP2, MMP9) and the expression of inflammatory factors (such as IL1β and IL6), and disrupting the structural integrity of the aortic wall. Furthermore, C-176 (a selective cGAS-STING pathway inhibitor) and STING-targeting siRNA synergistically reversed the NiCl₂-induced phenotypic transition of VSMCs, while VBIT12, an inhibitor of VDAC1, could also inhibit mtDNA leakage. This study is the first to reveal a novel mechanism by which NiCl₂ regulates VSMC dysfunction through the VDAC1-cGAS-STING axis. Our results identify NiCl 2 as a synergistic co-factor that, in conjunction with pre-existing vascular fragility (the 'first hit'), significantly accelerates AD progression through this molecular 'second hit', providing new targets and a theoretical basis for the prevention and treatment of cardiovascular diseases associated with NiCl₂ exposure.
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高影响因子
Materials Today Bio
·
2026
·
IF 11
Yi Cai,Cai-Yun Wang,Min Dong,Zhang Lin,Cai-Qiang Liao,Ze-Jun Li,Tian-Yi Qin,Zhao-Hui Wang,Ya-Long Wang,Ming-Qiang Zhu
The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a central driver of antitumor immunity, yet its safe and efficient activation in solid tumors remains challenging. Here we report a V-shaped photosensitizer, 2C6, that functions as an in situ DNA-fragmentation agent by directly targeting double-stranded DNA (dsDNA). Owing to its A–π–D–π–A molecular framework, 2C6 exhibits efficient reactive oxygen species (ROS) generation under low-power white-light irradiation. Photoactivation of 2C6 induces concurrent mitochondrial and nuclear DNA damage, leading to the accumulation of oxidized dsDNA fragments in the cytosol, which is closely associated with activation of the cGAS–STING signaling pathway. In parallel, 2C6-PDT induces pyroptosis and immunogenic cell death (ICD), as evidenced by elevated levels of pyroptosis-associated markers (including NLRP3, cleaved caspase-1, and GSDMD), along with features of ICD such as CRT exposure, ATP secretion, and HMGB1 release. In a murine 4T1 triple-negative breast cancer (TNBC) postsurgical residual model, a single intraoperative 2C6-PDT prevented local tumor recurrence, established immune memory within the observation period, and suppressed distant tumor growth and lung metastasis without immunoadjuvants. Collectively, 2C6 couples photoinduced DNA damage to cytosolic dsDNA sensing, type I interferon signaling, and adaptive immune activation through a defined cascade encompassing DNA damage, dsDNA accumulation, cGAS-STING engagement, inflammatory signaling, and immune-cell infiltration. Together, these findings demonstrate that rationally engineered DNA-targeted photosensitizers can convert localized photodynamic tumor ablation into a systemic photoimmunotherapeutic response, providing a strategy to transform immunologically “cold” tumors into immune-responsive states.
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高影响因子
Matter
·
2023
·
IF 18.9
Zhiqin Cao,Lanfang Ren,Le Niu,Rui Zhao,Nanhui Liu,Qi Zhuang,Feng Pan,Zhuang Liu,Yiyun Cheng,Yang Yang,Qian Chen
Summary Cancer vaccines have attracted tremendous interest in the field of cancer immunotherapy due to their ability to trigger tumor-specific immune responses to destroy cancer cells. Herein, we demonstrate that dendrimers coordinated with manganese ions (GT-Mn 2+ ) could self-assemble with peptides to form a cancer vaccine, which could be internalized by dendritic cells (DCs) via specific macropinocytosis-dependent and lipid-raft-related pathways and then dissociated gradually to release peptides to achieve efficient antigen cross-presentation and stimulate the cGAS-STING pathway. Additionally, GT-Mn 2+ could package multiple neoantigens to form an effective “personalized” cancer vaccine and has exhibited excellent therapeutic effects when used in combination with anti-PD-L1. Thus, our work presents an innovative peptide carrier to construct an effective “personalized” cancer vaccine that shows great promise to achieve effective cancer immunotherapy for different patients in clinic.
研究领域:
癌症免疫疗法
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纳米医学
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疫苗学
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高影响因子
Advanced Science
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2026
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IF 14.1
Bolun Xu,Xuan Lu,Yuquan Wang,Haihua Ji,Ying Zhang,Yiqun Wan,Hao Wan
Immunogenic cell death (ICD)-based whole-cell personalized cancer immunotherapies present full tumor antigens but suffer from poor immunogenicity, early clearance, and a glutathione (GSH)-rich immunosuppressive tumor microenvironment (TME). Here, we report a TME-responsive immunotherapeutic platform, DTBEI@CS@MnO 2 , which integrates immunogenicity-enhanced dead tumor cell bodies (DTBEI) with Mn 2 + -potentiated innate immunity. Tumor cells preloaded with indocyanine green (ICG) are sequentially functionalized with a chitosan (CS) interlayer followed by MnO 2 adsorption (CS@MnO 2 ) via electrostatic interactions. Upon near-infrared laser irradiation, ICG-mediated photodynamic/photothermal effect induces potent ICD, generating DTBEI. Within the acidic and GSH-enriched TME, the CS@MnO 2 coating disassembles to release DTBEI and MnO 2 . DTBEI provides endogenous antigens and ICD-associated danger signals, while MnO 2 is reduced by GSH to Mn 2 + . The resulting Mn 2 + amplifies DTBEI- and tumor-derived deoxyribonucleic acid-triggered cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation and downstream immune-stimulatory effects, thereby synergistically promoting dendritic cell maturation, antigen cross-presentation, and tumor-specific T-cell priming. Consequently, DTBEI@CS@MnO 2 elicits durable anti-tumor immunity, effectively inhibiting tumor growth and suppressing recurrence and metastasis, while establishing T-cell memory responses. Importantly, this strategy shows broad applicability in multiple tumor models, including CT26 colon cancer, 4T1 breast cancer, and B16F10 melanoma, while maintaining favorable biocompatibility. Overall, these findings highlight a materials-based approach for personalized cancer immunotherapy.
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