ADVANCED MATERIALS
·
2025
·
IF 26.8
Bin Liu,Xiaorui Chen,Yanlin Zhu,Hao Chen,Jia Tan,Zhuang Yang,Jing Li,Pan Zheng,Lili Feng,Qingqing Wang,Shili Gai,Lei Zhong,Piaoping Yang,Ziyong Cheng,Jun Lin
To improve the efficiency and application prospects of metal peroxides in tumor therapy, the synthesis of bimetallic peroxides via simple yet effective approaches will be highly significant. In this work, hyaluronic acid modified zinc-copper bimetallic peroxides (ZCPO@HA) nanoparticles are synthesized through a one-step symbiotic method by co-hydrolysis of zinc acetate and copper acetate in weakly alkaline solution, followed by modification with sodium hyaluronate. Upon decomposition in the tumor microenvironment, ZCPO@HA nanoparticles can generate a considerable content of hydroxyl radical (·OH) by Fenton-like reaction between Cu 2+ and self-compensating hydrogen peroxide, while downregulating the expression of glutathione peroxidase 4 to induce ferroptosis. The abundant release of Cu 2+ leads to the aggregation of dihydrolipoamide S-acetyltransferase and the reduction of iron-sulfur cluster proteins, causing cuproptosis. The immunogenic cell death of tumor cells releases abundant damage associated molecular patterns, effectively activating the adaptive immune response. Zn 2+ and ·OH cause mitochondrial damage, leading to the release of a substantial amount of mitochondrial DNA. This subsequently activates the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, enhancing the innate immune response. In conclusion, it synthesizes a new type of bimetallic peroxides by one-step symbiosis for activating anti-tumor immunotherapy combined with immune checkpoint inhibitor.
研究领域:
生物化学
·
肿瘤学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2022
·
IF 5.016
Alan Xu,Ruoxi Yang,Mingfei Zhang,Xiang Wang,Yuxi Di,Baoping Jiang,Yongxiang Di,Zhanwei Zhou,Lingling Zhou
The abundant M1 macrophages in the joint synovium were the main factors that exacerbate rheumatoid arthritis (RA) by secreting various types of inflammatory cytokines. Here, we note that cGAS-STING, an important pro-inflammatory pathway, was significantly up-regulated in RA, enabling it be the potential target for RA therapy. Therefore, in this work, we developed M1 macrophages targeted micelles capable of cGAS-STING pathway inhibition for the smart treatment of RA. The folic acid (FA) and lauric acid (LA) were modified on dextran to obtain an amphiphilic polymer (FDL). Then, FDL was subsequently applied to encapsulate triptolide (TP) to form FDL@TP nanomicelles. The FDL@TP could target the joint and enhance the cell uptake of TP by M1 macrophages (overexpressing folate receptor-β), which also reduced the side effects of TP on normal tissues. In M1 macrophages, the released TP, acted as an anti-inflammatory and immunosuppressant, obviously down-regulated the expressions of cGAS and STING protein, and thus reduced the secretion of TNF-α, IL-1β and IL-6. Importantly, compared with the same dose of free TP, FDL@TP could significantly enhance the anti-inflammatory effect. Therefore, FDL@TP nanomicelles were believed to be superior candidates for the clinical treatment of RA.
研究领域:
药理学
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免疫学
·
纳米技术
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风湿病学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2022
·
IF 15.304
Lei Cao,Huixiang Tian,Man Fang,Zhe Xu,Dongsheng Tang,Juan Chen,Jiye Yin,Haihua Xiao,Kun Shang,Hongbin Han,Xiangping Li
cGAS-STING pathway, as an essential intracellular immune response pathway, has attracted much attention in tumor immunotherapy. However, low metabolic stability of conventional STING agonists limits their clinical application. Recent study shows that chemotherapeutic drugs cisplatin and camptothecin (CPT) can activate cGAS-STING pathway and induce immune response by DNA damage. Nevertheless, the ability of chemotherapeutic drugs to activate STING is so weak that new strategies are required to improve drug delivery efficiency for enhanced DNA damage, and then efficiently activate cGAS-STING pathway. Herein, we have developed a hybrid platinum prodrug (CPT-Pt (IV)) which can be triggered to release cisplatin and CPT in tumor cells. CPT-Pt (IV) with high hydrophobicity is further self-assembled with a ROS sensitive polymer (P1) and mPEG 2k -DSPE into ROS responsive nanoparticles (NPs). NPs could accumulate in the tumor site to release cisplatin and CPT, resulting in DNA double damage and finally activating cGAS-STING pathway, inducing DC cells maturation and increasing tumor infiltration of CD8 + T cells on colorectal cancer mouse model. This study showed that common DNA targeted drugs can activate the cGAS-STING pathway in situ via nano delivery system, and enhance the effect of chemotherapy and immunotherapy, which provide a new strategy for clinical antitumor therapy.
研究领域:
肿瘤学
·
药学
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免疫学
·
纳米技术
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Ke Zhang,Chengyao Huang,Yu Ren,Mingyue Zhang,Xiaotong Lu,Bangliu Yang,Peiran Chen,Shiyao Guo,Xueqian Wang,Yuhong Zhuo,Chao Qi,Kaiyong Cai
Tumor immunotherapy represents one of the most promising strategies for combating tumors by activating the immune system, harnessing anti-tumor immune cells to eliminate tumor cells, and preventing tumor recurrence and metastasis. However, clinical data indicate that the anti-tumor immune response is often inadequate in many cancer patients, resulting in the failure of tumor immunotherapy. Herein, we report a manganese (Mn)-based nanoadjuvant (denoted as BMP-Au) aimed at synergistically enhancing anti-tumor immune responses in breast cancer therapy through disulfidptosis-induced immunogenic cell death and Mn-mediated cGAS-STING pathway activation. BMP-Au is synthesized using bovine serum albumin as a biotemplate for biomimetic mineralization of manganese phosphate nanosheets, followed by the deposition of gold nanoparticles (Au NPs) on their surface. By exploiting the glucose oxidase-like activity of Au NPs alongside the Fenton-like reaction facilitated by Mn 2+ , BMP-Au orchestrates a cascade catalytic reaction that generates reactive oxygen species from glucose. This process not only initiates disulfidptosis but also leads to DNA fragmentation crucial for activating the cGAS-STING pathway. These concurrent mechanisms compromise cancer cell viability while significantly enhancing tumor immunogenicity, positioning BMP-Au as an innovative nanoadjuvant for cancer treatment that leverages both cellular stress mechanisms and immune activation.
研究领域:
肿瘤免疫学
·
纳米医学
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生物材料学
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产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2025
·Vol. 10
·期 1
·1-17
·
IF 52.7
Tang Yu,Luo Zhiyuan,Ma Zhanni,Han Lingling,Zhou Yurong,Liang Tianci,Yang Kangsen,Zhao Lei,Chen Xiaoyuan,Zhang Pengfei
The variety and functionality of current clinical vaccine adjuvants remain limited. Conventional aluminum-based adjuvants predominantly induce Th2-biased humoral immunity but exhibit a limited capacity to elicit Th1-mediated cellular immune responses, particularly tumor antigen-specific cytotoxic CD8 + T lymphocytes (CTLs), which are essential for effective cancer vaccine performance. Inspired by natural biomolecular condensates, we developed a versatile noncovalent protein self-assembly strategy distinct from traditional approaches requiring structural domain modifications or bifunctional crosslinkers. Our methodology employs amphiphilic molecules (sodium myristate/SMA and sodium dodecyl thiolate/SDT) as molecular bridges to mediate protein‒protein interactions through hydrophobic forces and disulfide bond formation. This process generates nanoscale protein condensate (PCD) vaccines with exceptional stability. As a novel adjuvant system, these synthetic condensates significantly enhance antigen cross-presentation by optimizing key parameters: antigen loading capacity, lymph node targeting, cytosolic delivery, and lysosomal escape. Consequently, they induce robust antigen-specific CTL responses and humoral immunity, demonstrating potent antitumor efficacy. Importantly, we found that the synthetic protein condensate (PCD) alone can act as a nanoadjuvant. By increasing mitochondrial membrane permeability, PCD induces mitochondrial DNA leakage into the cytosol, activating the cGAS‒STING pathway and promoting DC maturation. This safe and scalable platform eliminates the need for complex covalent modifications or genetic engineering, and it facilitates the design of diverse modular antigens, including neoantigens and viral antigens. Given its straightforward manufacturing process and superior immunogenicity, this synthetic PCD vaccine adjuvant has significant potential for clinical application and translation.
研究领域:
免疫学
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肿瘤学
·
纳米医学
·
分子生物学
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转化医学
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疫苗学
✓ 已验证
产品关联
DOI
PubMed
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
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Xiaowen Hou,Chunlin Ren,Xiaodong Zeng,Yukun Hu,Yicheng Zhao,Yuxin Cheng,Qiusi Luo,Taotao Ding,Xue Qiao,Yuqin Liao,Guo-Bo Li,Bengui Ye,Xuechuan Hong,Yuling Xiao
DNA-targeting chemotherapies can activate the stimulator of interferon genes (STING) pathway but elicit limited immune responses. We engineered 3P-SN38 , a long-circulating nanoplatform enabling sustained, tumor-targeted SN38 delivery and NIR-II imaging. To further potentiate immune activation and minimize STING agonist toxicity, SR717 was co-encapsulated, forming 3P-SN38@SR717 . 3P-SN38@SR717 induced immunogenic cell death and dendritic cell maturation in vitro , with combination therapy showing superior effects. In vivo , 3P-SN38@SR717 effectively activated the cGAS-STING pathway, enhancing anti-tumor immunity. Significant increases in the populations of CD8 + T cells, mature dendritic cells, and M1-type macrophages were observed, along with elevated levels of cytokines, including IL-6 and TNF-α. This integrated nanoplatform offers a promising approach for chemoimmunotherapy, enabling durable tumor control with reduced dosing and improved safety.
研究领域:
纳米医学
·
免疫治疗
·
肿瘤学
·
药学
·
生物医学成像
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Yuchen Zhang,Shuang Feng,Jie Luo,Kaige Xu,Junfeng Guo,Xingyue Zhang,Mengxue Yuan,Qiang Luo,Yu Huang,Chaoqiang Fan,Kibret Mequanint,Donghui Zhu,Malcolm Xing,Shiming Yang
The cGAS-STING signaling pathway effectively activates antitumor immune responses and holds promise for overcoming drug resistance in hepatocellular carcinoma (HCC) immunotherapy. However, achieving specific activation of this pathway in HCC remains challenging. Here, it is introduced a single-metal-doped nanoplatform, ZMRPF, which leverages ferroptosis-induced mitochondrial DNA (mtDNA) release to stimulate cGAS-STING-mediated immune activation. ZMRPF initiates HCC ferroptosis by inducing high levels of lipid reactive oxygen species, leading to mitochondrial stress and the release of endogenous mtDNA. This mtDNA synergistically activates the cGAS-STING pathway, enhanced by immunoactivating Mn 2 ⁺ ions released from ZMRPF. Concurrently, the tumor antigens released during ferroptosis amplify the activity of antigen-presenting cells, creating a cascade that links ferroptosis with innate immunity. This cascade drives a robust systemic antitumor immune response, effectively reversing the immunosuppressive microenvironment of HCC. These results demonstrate the ability of ZMRPF to reshape the immune microenvironment of HCC and offer a promising strategy for next-generation tumor immunotherapy.
研究领域:
肿瘤学
·
免疫治疗
·
纳米医学
·
分子生物学
·
癌症免疫学
✓ 已验证
产品关联
DOI
高影响因子
Oxidative Medicine and Cellular Longevity
·
2022
·
IF 7.31
Lu Bai,Jing Dai,Yuxuan Xia,Kaichuan He,Hongmei Xue,Qi Guo,Danyang Tian,Lin Xiao,Xiangjian Zhang,Xu Teng,Yuming Wu,Sheng Jin
Although it is an essential nutrient, high choline intake directly or indirectly via its metabolite is associated with increased risk of cardiovascular disease, the mechanism of which remains to be elucidated. The present study was performed to investigate whether hydrogen sulfide (H2S) was involved in high choline-induced cardiac dysfunction and explore the potential mechanisms. We found that ejection fraction (EF) and fractional shortening (FS), the indicators of cardiac function measured by echocardiography, were significantly decreased in mice fed a diet containing 1.3% choline for 4 months as compared to the control, while applying 3,3-dimethyl-1-butanol (DMB) to suppress trimethylamine N-oxide (TMAO, a metabolite of choline) generation ameliorated the cardiac function. Subsequently, we found that feeding choline or TMAO significantly increased the protein levels of cyclic GMP-AMP (cGAMP) synthase (cGAS), stimulator of interferon genes (STING), NOD-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1β (IL-1β) as compared to the control, which indicated the activation of cGAS-STING-NLRP3 inflammasome axis. Moreover, the protein expression of cystathionine γ-lyase (CSE), the main enzyme for H2S production in the cardiovascular system, was significantly increased after dietary supplementation with choline, but the plasma H2S levels were significantly decreased. To observe the effect of endogenous H2S, CSE knockout (KO) mice were used, and we found that the EF, FS, and plasma H2S levels in WT mice were significantly decreased after dietary supplementation with choline, while there was no difference between CSE KO + control and CSE KO + choline group. To observe the effect of exogenous H2S, mice were intraperitoneally injected with sodium hydrosulfide (NaHS, a H2S donor) for 4 months, and we found that NaHS improved the cardiac function and reduced the protein levels of cGAS, STING, NLRP3, caspase-1, and IL-1β in mice receiving dietary choline. In conclusion, our studies revealed that high choline diet decreased plasma H2S levels and induced cardiac dysfunction via cGAS-STING-NLRP3 inflammasome axis while H2S treatment could restore the cardiac function by inhibiting cGAS-STING-NLRP3 inflammasome axis.
研究领域:
心脏病学
·
营养学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Ying Xiang,Jinyu Zheng,Xinlu Zhao,Lina Zhou,Qiong Yan,Yichun Ma,Yue Zhou,Ping Jiang,Yi Fang,Wenjun Li,Yinya Pan,Hongji Tao,Wenying Li,Fan Xiang,Yang Hua,Yuyi Li,Chang Zheng,Weihong Ge,Yuhong Li,Simin Yan,Yun Zhu,Guifang Xu
While much attention has been focused on the direct cytotoxic effects of anticancer agents on tumor cells, emerging evidence suggests that the induction of immunogenic cell death (ICD) and the consequent remodeling of the tumor microenvironment may critically influence overall therapeutic efficacy. Sorafenib, a multitargeted tyrosine kinase inhibitor, can induce ferroptosis and thereby trigger ICD, offering the potential to overcome chemoresistance and coordinate systemic antitumor immunity. However, its therapeutic efficacy in colorectal cancer (CRC) remains limited, attributing to its low efficiency in inducing ICD. Herein, this study investigates combined sodium butyrate (NaB) and sorafenib in liposomal co-delivery system (LipNaB@Sor) at an optimal 1:1 molar ratio in CRC. LipNaB@Sor synergistically amplifies sorafenib-induced ferroptosis and consequent ICD, concurrently activating antitumor immunity through dendritic cell maturation and cytotoxic CD8 + T cell recruitment. Mechanistically, IRF2-mediated Oasl2 downregulation activates the cGAS-STING pathway, augmenting DNA damage signaling cascades. In vivo validation demonstrates significant tumor suppression and prolonged survival without observable toxicity, establishing LipNaB@Sor as a translatable strategy to overcome therapy resistance in immunologically unresponsive CRC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2025
·
IF 26.3
Zhimeng Wang,Yanfei Hou,Peiyuan Liu,Ruinan Wu,Jiaming Yang,Shilong Fan,Zexu Peng,Xiaoxu Han,Bin Su,Conggang Zhang
The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway mediates antiviral innate immunity upon sensing cytosolic DNA. Here, we examined the impact of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a paralog of the LXR lipid metabolism-induced cGAMP-degrading enzyme SMPDL3A, on viral infection. We found that SMPDL3B was induced and stabilized by both viral infection and membrane-disturbing agents, suggesting a role in sensing membrane stress as an early signal of cellular danger. Deletion of SMPDL3B impaired DNA virus infection. Upon induction, SMPDL3B suppressed cGAS-STING signaling and downstream transcriptional pathways, including the interferon response. Mechanistically, SMPDL3B functioned as a cGAMP hydrolase; cGAMP-induced SMPDL3B dimerization enabled its hydrolase activity and a negative feedback loop that dampened STING signaling. SMPDL3B-deficient cells had elevated cGAMP concentrations, and Smpdl3b −/− mice exhibited enhanced cGAMP accumulation, heightened immune activation, and reduced viral loads upon herpes simplex virus type 1 (HSV-1) infection. Thus, SMPDL3B links membrane stress to modulation of cGAS-STING signaling through cGAMP degradation, with potential implications in the contexts of inflammation or autoimmunity.
研究领域:
免疫学
·
病毒学
·
细胞生物学
·
先天免疫
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2023
·
IF 8.8
Lihui Xuan,Yin Wang,Can Qu,Yuhui Yan,Wensen Yi,Jingjing Yang,Magdalena Skonieczna,Cuimei Chen,Justyna Miszczyk,Dmitry S. Ivanov,Hesham M.H. Zakaly,Vladimir Markovic,Ruixue Huang
Nanoplastics have been widely studied as environmental pollutants, which can accumulate in the human body through the food chain or direct contact. Research has shown that nanoplastics can affect the immune system and mitochondrial function, but the underlying mechanisms are unclear. Lungs and macrophages have important immune and metabolic functions. This study explored the effects of 100 nm PS-NPs on innate immunity, mitochondrial function, and cellular metabolism-related pathways in lung (BEAS-2B) cells and macrophages (RAW264.7). The results had shown that PS-NPs exposure caused a decrease in mitochondrial membrane potential, intracellular ROS accumulation, and Ca 2+ overload, and activated the cGAS-STING signaling pathway related to innate immunity. These changes had been observed at concentrations of PS-NPs as low as 60 μg/mL, which might have been comparable to environmental levels. Non-target metabolomics and Western Blotting results confirmed that PS-NPs regulated prostaglandin B1 and other metabolites to cause cell damage through the cGAS-STING pathway. Supplementation of prostaglandin B1 alleviated the immune activation and metabolic disturbance caused by PS-NPs exposure. This study identified PS-NPs-induced innate immune activation, mitochondrial dysfunction, and metabolic toxicity pathways, providing new insights into the potential for adverse outcomes of NPs in human life.
研究领域:
环境科学
·
免疫学
·
细胞生物学
·
代谢组学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）