Journal of Materials Chemistry B
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2023
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IF 7
Qi Long,Yuliang Yang,Fangling Liao,Haoting Chen,Dongyue He,Shengliang Li,Li Pengcheng,Weisheng Guo,Yafang Xiao
Photothermal immunotherapy has shown great potential for efficient cancer treatment. However, the immunosuppressive tumor microenvironment forms a heavy barrier for photothermal-induced anti-tumor immunity by inhibiting dendritic cells (DCs) maturation and cytotoxic T cell response. Moreover, the lack of reliable spatiotemporal imaging modalities makes photothermal immunotherapy difficult to guide tumor ablation and monitor the therapeutic outcomes in real time. Herein, we designed a theranostic thermosensitive liposome (PLDD) as a versatile nanoplatform to boost adaptive anti-tumor immunity of photothermal immunotherapy and achieve multiple bioimaging modalities in a real-time manner. The PLDD contains two major functional components: a multifunctional photothermal agent (DTTB) and an immune potentiator STING pathway agonist (DMXAA). Upon irradiation, the heat generated by DTTB induced the immunogenic cell death (ICD) of the tumor and dissociated the structure of thermosensitive liposome to release DMXAA, which ultimately activated the STING pathway and promoted the ICD-induced immune response by increasing DC cells maturation and T cell recruitment. Meanwhile, the DTTB in PLDD displayed excellent second near-infrared (NIR-II) fluorescence and photoacoustic (PA) dual-modal imaging, which provided omnibearing information on the tumor and guided the subsequent therapeutic operation. Therefore, this versatile PLDD with light-triggered promotion of anti-tumor immunity and multiple spatiotemporal imaging profiles holds great potential for the future development of cancer immunotherapy.
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International Journal of Nanomedicine
·
2024
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IF 6.6
Xiaomei Jiang,Xiaohong Jiang,Dongjie Wu,Wanzhu Xie,Xiong Liu,Jintao Zheng
Background Radiotherapy is a widely used clinical tool for tumor treatment but can cause systemic toxicity if excessive radiation is administered. Although numerous nanoparticles have been developed as radiosensitizers to reduce the required dose of X-ray irradiation, they often have limitations, such as passive reliance on radiation-induced apoptosis in tumors, and little consider the unique tumor microenvironment that contributes radiotherapy resistance.Methods In this study, we developed and characterized a novel self-assembled nanoparticle containing dysprosium ion and manganese ion (Dy/Mn-P). We systematically investigated the potential of Dy/Mn-P nanoparticles (NPs) as a reactive oxygen species (ROS) amplifier and radiosensitizer to enhance radiation therapy and modulate the tumor microenvironment at the cellular level. Additionally, we evaluated the effect of Dy/Mn-P on the stimulator of interferon genes (STING), an innate immune signaling pathway.Results Physicochemical analysis demonstrated the prepared Dy/Mn-P NPs exhibited excellent dispersibility and stability, and degraded rapidly at lower pH values. Furthermore, Dy/Mn-P was internalized by cells and exhibited selective toxicity towards tumor cells compared to normal cells. Our findings also revealed that Dy/Mn-P NPs improved the tumor microenvironment and significantly increased ROS generation under ionizing radiation, resulting in a ~70% increase in ROS levels compared to radiation therapy alone. This enhanced ROS generation inhibited ~92% of cell clone formation and greatly contributed to cytoplasmic DNA exposure. Subsequently, the activation of the STING pathway was observed, leading to the secretion of pro-inflammatory immune factors and maturation of dendritic cells (DCs).Conclusion Our study demonstrates that Dy/Mn-P NPs can potentiate tumor radiotherapy by improving the tumor microenvironment and increasing endogenous ROS levels within the tumor. Furthermore, Dy/Mn-P can amplify the activation of the STING pathway during radiotherapy, thereby triggering an anti-tumor immune response. This novel approach has the potential to expand the application of radiotherapy in tumor treatment.
研究领域:
纳米技术
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癌症治疗
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放射生物学
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免疫治疗
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ACS Nano
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2023
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IF 17.1
Anwei Zhou,Kerong Chen,Ya Gao,Xinyuan Zhou,Zihan Tian,Weiwei Chen,Yurui Xu,Zhuo Chen,Xinghai Ning
Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute to high mortality rates. However, current treatment approaches exhibit limited potential to balance immune response and overproduction of inflammatory cytokines, leading to poor therapeutic outcomes. Herein, a smart bioengineered neutrophil, Extinguisher, composed of live neutrophils encapsulating the liposome formulation of NF-κB suppressor MLN4924 and STING inhibitor H-151 (Lip@MH), is developed for alleviating the hyperinflammatory cytokine storm. Extinguisher inherits motility and chemotaxis characteristics of neutrophils, allowing for the specific delivery and sustained release of Lip@MH within inflamed tissues. Subsequently, Lip@MH effectively transports anti-inflammatory agents into macrophages and synergistically inhibits inflammatory pathways of NF-κB and STING, leading to decreased production of cytokines. In vivo studies demonstrate that Extinguisher not only selectively accumulates at the site of pneumonia caused by Pseudomonas aeruginosa-induced acute lung injury but inhibits the production of inflammatory factors through regulating NF-κB/STING signaling pathways, thereby effectively calming cytokine storm. Importantly, Extinguisher significantly improves therapeutic benefits and survival in mice with acute pneumonia. Therefore, Extinguisher represents an appropriate combination of cell therapy and immunoregulation for cytokine storm intervention and may bring insights into the treatment of COVID-19 pneumonia.
研究领域:
免疫学
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生物技术
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药学
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分子生物学
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Frontiers in Pharmacology
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2022
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IF 5.988
Zhang Cong,Song Yingying,Chen Liang,Chen Peng,Yuan Ming,Meng Yan,Wang Qi,Zheng Guohua,Qiu Zhenpeng
Urolithin A (UroA) is one of the primary intestinal metabolites of ellagitannins, showing translational potential as a nutritional intervention in humans. Mounting evidence suggests that fructose consumption contributes to the progression of chronic kidney disease (CKD) that manifests in hyperuricemic nephropathy, renal inflammation, and tubulointerstitial injury. Here, we investigated the efficacy of UroA in alleviating fructose-induced hyperuricemic nephropathy in mice. Uric acid-exposed human kidney-2 (HK-2) cells were utilized for in vitro mechanism validation. Histopathological staining, immunoblotting, and transmission electron microscope were performed for the mechanistic investigations. Our results revealed that UroA ameliorated fructose-induced hyperuricemic nephropathy in mice. The histopathologic assessment showed that UroA attenuated tubular hypertrophy and dilation, glomerular basement membrane thickening, and collagen deposition in the kidney of fructose-fed mice. Mechanistically, UroA treatment impaired STING-NLRP3 activation, resulting in reduced production of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Notably, UroA exhibited a scavenging effect against reactive oxygen species (ROS) and restored fructose-impaired PINK1/Parkin-mediated mitophagy in nephropathic mice. Furthermore, the inhibitory effect of UroA in STING-NLRP3 activation was impaired after Parkin gene silencing in HK-2 cells. Together, this study suggests that UroA alleviates fructose-induced hyperuricemic nephropathy by promoting Parkin-dependent mitophagy, thereby suppressing STING-NLRP3 axis-mediated inflammatory response. Thus, dietary supplementation with UroA or ellagitannins-rich foods may serve as a promising intervention to prevent CKD progression.
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Bioactive Materials
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2024
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IF 18
Guanyu Jin,Hao Liu,Zi Mei,Qionghua Jin,Sheng Ma,Lanqing Wang,Yuanzhen Su,Letian Lv,Zijuan Wang,Huicong Zhou,Mingqiang Li,Zehuan Huang,Xuesi Chen,Shixian Lv
Tumor recurrence and metastasis after surgery are important factors affecting patient survival. The immunosuppressed tumor microenvironment after surgery reduces the ability of the immune system to clear residual tumor cells, thus increasing the risk of recurrence and metastasis. Currently, immunotherapy-based adjuvant therapy can effectively inhibit tumor recurrence and metastasis after surgery, but simultaneous and efficient synergistic activation of adaptive and innate immunity is a challenge. Here, we utilized polymeric hydrogel loaded with decitabine (DAC), cisplatin (CDDP) and manganese ions (Mn 2+ ) as a postoperative filler immunogel to synergistically activate both anti-tumor innate and adaptive immunity. The sustained release of CDDP and DAC burst gasdermin E (GSDME)-mediated pyroptosis and activated adaptive immunity, while Mn 2+ enhanced intrinsic immune activation through STING pathway. Such immunogel achieved an encouraging anti-tumor effect with an 80 % total survival rate for recurrent tumors and a 60 % survival rate for metastatic tumors. Considering that this in situ immunogel possesses simple formulation and displays superior anti-tumor effect, this research provided a promising strategy for postoperative cancer 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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BIOMATERIALS
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2024
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IF 12.8
Zishan Zeng,Yue Sun,Jingwen Jiang,Xiaoyu Xu,Huanxin Lin,Wanzhen Li,Dong Zheng,Yanjuan Huang,Chunshun Zhao
Gastric cancer constitutes a malignant neoplasm characterized by heightened invasiveness, posing significant global health threat. Inspired by the analysis that gastric cancer patients with Helicobacter pylori ( H. pylori ) infection have higher overall survival, whether H. pylori can be used as therapeutics agent and oral drug delivery system for gastric cancer. Hence, we constructed engineered H. pylori for gastric cancer treatment. A type Ⅱ H. pylori with low pathogenicity, were conjugated with photosensitizer to develop the engineered living bacteria NIR-triggered system (Hp-Ce6). Hp-Ce6 could maintain activity in stomach acid, quickly infiltrate through mucus layer and finally migrate to tumor region owing to the cell morphology and urease of H. pylori . H. pylori, accumulated in the tumor site, severed as vaccine to activate cGAS-STING pathway, and synergistically remodel the macrophages phenotype. Upon irradiation within stomach, Hp-Ce6 directly destroyed tumor cells via photodynamic effect inherited by Ce6, companied by inducing immunogenic tumor cell death. Additionally, Hp-Ce6 exhibited excellent biosafety with fecal elimination and minimal blood absorption. This work explores the feasibility and availability of H. pylori -based oral delivery platforms for gastric tumor and further provides enlightening strategy to utilize H. pylori invariably presented in the stomach as in-situ immunomodulator to enhance antitumor efficacy.
研究领域:
肿瘤学
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药学
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免疫学
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生物技术
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Asian Journal of Pharmaceutical Sciences
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2024
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IF 10.7
Shengnan Huang,Chenyang Zhou,Chengzhi Song,Xiali Zhu,Mingsan Miao,Chunming Li,Shaofeng Duan,Yurong Hu
Postoperative tumor recurrence remains a predominant cause of treatment failure. In this study, we developed an in situ injectable hydrogel, termed MPB-NO@DOX + ATRA gel, which was locally formed within the tumor resection cavity. The MPB-NO@DOX + ATRA gel was fabricated by mixing a thrombin solution, a fibrinogen solution containing all-trans retinoic acid (ATRA), and a Mn/NO-based immune nano-activator termed MPB-NO@DOX. ATRA promoted the differentiation of cancer stem cells, inhibited cancer cell migration, and affected the polarization of tumor-associated macrophages. The outer MnO 2 shell disintegrated due to its reaction with glutathione and hydrogen peroxide in the cytoplasm to release Mn 2+ and produce O 2 , resulting in the release of doxorubicin (DOX). The released DOX entered the nucleus and destroyed DNA, and the fragmented DNA cooperated with Mn 2+ to activate the cGAS-STING pathway and stimulate an anti-tumor immune response. In addition, when MPB-NO@DOX was exposed to 808 nm laser irradiation, the Fe-NO bond was broken to release NO, which downregulated the expression of PD-L1 on the surface of tumor cells and reversed the immunosuppressive tumor microenvironment. In conclusion, the MPB-NO@DOX + ATRA gel exhibited excellent anti-tumor efficacy. The results of this study demonstrated the great potential of in situ injectable hydrogels in preventing postoperative tumor recurrence.
研究领域:
肿瘤学
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生物材料学
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免疫学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Zheng Jia,Xinyao Zhou,Jingjing Liu,Xinqi De,Yifan Li,Zaixing Yang,Haoyuan Duan,Fang Wang,Junwei Ge
The use of biomimetic mineralization strategy is promising to solve the problem of poor stability and immune effect of subunit antigens. However, non-specifically inducing protein mineralization is still a challenge. we hypothesized that rhamnolipids with both protein and metal binding capacity could be used to develop more functional and biocompatible calcium mineralized nanoparticle (RMCP). The results show that rhamnolipids synergistically enhanced the mineralization of protein with manganese ions and improved 21 % the loading antigens of RMCP compared to manganese calcium phosphate nanoparticles. Transmission electron microscopy (TEM) and Dynamic Light Scattering (DLS) showed particle size of RMCP is 260 ± 12.1 nm with spherical morphology. In vitro experiments have shown that RMCP effectively activate immune cells through the cGAS-STING and NLRP3 pathways and demonstrated a higher level of cytokines in RAW264.7 Macrophages. In vivo, RMCP triggered an increased IgG titer with 16.5-fold IgG2a/IgG1 ratio compared to the aluminum adjuvant which improved the recovery status after challenge in mice. We used biological surfactants for the first time to enhance the biomimetic mineralization process of subunit antigen, which provides a new approach for constructing calcium-based biocompatible antigen delivery vectors, helping to develop a new generation of stable, efficient, and safe subunit vaccines.
研究领域:
免疫学
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纳米技术
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疫苗开发
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生物材料
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Materials Today Bio
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2026
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IF 11
Jing P,Wang L,Qiu X,Chen L,Xie D,Yu Y,Li B,Yan S,Wang G,Zhong Z,Fu W.
Effective cancer immunotherapy relies on robust infiltration and sustained functionality of tumor-resident cytotoxic CD8 + T cells. Here we report a magnetic resonance imaging (MRI)-visible nanotheranostic that integrates redox modulation, inflammatory cell death, and innate immune sensitization to establish a self-amplifying pyroptosis-STING-IFN-β circuit for CD8 + T cell immunoactivation. The nanotheranostic is constructed through manganese ion (Mn 2+ )-catalyzed oxidative polymerization of polyphenols, enabling engineered reactive oxygen species (ROS) generation and localized metal ion availability. Functionally, intracellular ROS triggers caspase-3-dependent gasdermin E (GSDME) cleavage and pyroptosis, while concomitant mitochondrial perturbation increases cytosolic mitochondrial DNA (mtDNA) and sensitizes the cGAS-STING pathway to Mn 2+ -enhanced activation, resulting in IFN-β production. IFN-β further reinforces dendritic cells maturation and CD8 + T cells priming, whereas inflammatory pyroptosis amplifies mtDNA availability, together forming a self-amplifying positive-feedback circuit that magnifies antitumor immunity. In vivo , this coordinated mechanism promotes effective CD8 + T cells infiltration and memory formation. Owing to its high longitudinal relaxivity, the nanotheranostic enables clear T 1 -weighted MRI contrast with pronounced tumor accumulation and prolonged retention, supporting imaging-guided immunotherapy. This work presents a functional materials strategy that couples mechanistic immune amplification with diagnostic imaging, offering a conceptual framework for translatable immunotheranostics.
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Environment & Health
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2026
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IF 6.3
Shiyin Zhong,Qiongli Zhou,Jirui Yang,Zhimin Zhang,Xueting Chai,Jinghao Luo,Xin Zhang,Jingjing Liu,Yangzong Yixi,Lei Shi,Xuhong Chang,Hui Wang
Manganese (Mn) is an essential trace element, but increasing industrial and agricultural use has led to elevated levels of environmental Mn levels. Chronic overexposure to Mn can cause a Parkinson’s-like neurodegenerative disorder; however, the underlying mechanisms remain incompletely understood. This study combined in vitro and in vivo models to investigate the role of the cGAS–STING/NLRP3 axis in regulating the p38 MAPK/NF–κB pathway in the process of Mn-induced Tau aggregation leading to neurotoxicity. Our results demonstrated that MnCl2 exposure significantly activated both the cGAS–STING/NLRP3 signaling axis and the p38 MAPK/NF–κB pathway, accompanied by increased Tau expression. Genetic ablation of cGAS, STING, or NLRP3 attenuated Mn-induced Tau upregulation, indicating that the cGAS–STING/NLRP3 signaling axis mediates Tau expression. RNA-seq analysis further revealed that the decreased Tau expression in knockout cells is associated with the MAPK/NF–κB signaling pathway. Pharmacological inhibition of p38 MAPK or NF–κB markedly downregulated cGAS–STING signaling, inflammatory cytokine release, and phosphorylated Tau (p-Tau) levels. Moreover, we observed colocalization and interaction among p-p38, p-p65, and p-Tau. Overall, these findings reveal that Mn activates the cGAS–STING/NLRP3 signaling axis regulated by the p38 MAPK/NF–κB pathway, driving pathological Tau aggregation.
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Advanced Science
·
2022
·Vol. 9
·期 32
·2203523
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IF 17.521
Ming Shen,Chuanrong Chen,Qianqian Guo,Quan Wang,Jinghan Liao,Liting Wang,Jian Yu,Man Xue,Yourong Duan,Jiali Zhang
T-cell engagers (TCEs) represent a breakthrough in hematological malignancy treatment but are vulnerable to antigen escape and lack a vaccination effect. The “immunologically cold” solid tumor presents substantial challenges due to intratumor heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, a methoxy poly(ethylene glycol) (mPEG)-masked CD44×PD-L1/CD3 trispecific T-cell nanoengager loaded with the STING agonist c-di-AMP (CDA) (PmTriTNE@CDA) for the treatment of triple-negative breast cancer (TNBC) is rationally designed. PmTriTNE@CDA shows tumor-specific accumulation and is preferentially unmasked in response to a weakly acidic TME to prevent on-target off-tumor toxicity. The unmasked CD44×PD-L1/CD3 trispecific T-cell nanoengager (TriTNE) targets dual tumor-associated antigens (TAAs) to redirect CD8+ T cells for heterogeneous TNBC lysis while achieving PD-L1 blockade. PmTriTNE synergized with CDA to transform the cold tumor into a hot tumor, eradicate the large established TNBC tumor, and induce protective immune memory in a 4T1 orthotopic tumor model without causing obvious toxicity. PmTriTNE@CDA shows potent efficacy in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. This study serves as a proof-of-concept demonstration of a nanobased TCEs strategy to expand therapeutic combinations that previously could not be achieved due to systemic toxicity with the aim of overcoming TNBC heterogeneity and immunotherapy resistance.
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Journal of Inflammation Research
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2022
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IF 4.631
Renhui Huang,Qi Shi,Shutian Zhang,Hong Lin,Chengzhi Han,Xinyi Qian,Yijun Huang,Xiaorong Ren,Jiayuan Sun,Nana Feng,Chunmei Xia,Meng Shi
Purpose: Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS.Methods: We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system.Results: In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats.Conclusion: Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.
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