JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-19
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IF 10.6
Chen Yang,Tian Hailong,Zhang Xiaodian,Nice Edouard C.,Huang Canhua,Zhang Haiyuan,Zheng Shaojiang
Limited drug accumulation and an immunosuppressive microenvironment are the major bottlenecks in the treatment of glioblastoma multiforme (GBM). Herein, we report a copper-coordination driven brain-targeting nanoassembly (TCe6@Cu/TP5 NPs) for site-specific delivery of therapeutic agents and efficient immunotherapy by activating the cGAS-STING pathway and downregulating the expression of PD-L1. To achieve this, the mitochondria-targeting triphenylphosphorus (TPP) was linked to photosensitizer Chlorin e6 (Ce6) to form TPP-Ce6 (TCe6), which was then self-assembled with copper ions and thymopentin (TP5) to obtain TCe6@Cu/TP5 NPs. This nanoassembly effectively accumulated in tumor sites through the copper transport mechanism. Meanwhile, TCe6@Cu/TP5 could induce mitochondrial impairment by photodynamic therapy (PDT) mediated reactive oxygen species (ROS) accumulation and Cu 2+ triggered cuproptosis, resulting in evoking the AMP-activated protein kinase (AMPK) pathway to degrade PD-L1, and activating the cGAS-STING pathway to enhance anti-tumor immunity. Moreover, TP5 significantly promoted the proliferation and differentiation of dendritic cells (DCs) and T lymphocytes to further amplify the cancer immunity cycle. Collectively, our TCe6@Cu/TP5 NPs effectively facilitate drug accumulation and activate systemic antitumor immunity in vitro and in vivo, providing an innovative solution across the BBB that potentiates GBM immunotherapy. Graphical
研究领域:
癌症研究
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纳米技术
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免疫学
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神经科学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Research
·
2024
·
IF 8.1
Mingxiao Fang,Jun Zheng,Jingxue Wang,Chenpeng Zheng,Xiaojing Leng,E. Wen,Pan Li,Haitao Ran,Liang Zhang,Zhigang Wang
The field of immunotherapy, particularly immune checkpoint blockade (ICB), holds immense potential in mitigating the progression of cancer. However, the challenges of insufficient tumor antigen production and the immunosuppressive state in the tumor microenvironment substantially impede patients from deriving benefits. In this research, we present a tumor-microenvironment-modulation manganese-based nanosystem, PEG-MnMOF@PTX, aiming to improve the responsiveness of ICB. Under acidic conditions, the released Mn2+ accomplishes multiple objectives. It generates toxic hydroxyl radicals (•OH), together with the released paclitaxel (PTX), inducing immunogenic cell death of tumor cells and normalizing tumor blood vessels. Concurrently, it facilitates the in situ generation of oxygen (O2) from hydrogen peroxide (H2O2), ameliorating the microenvironmental immunosuppression and increasing the efficacy of immunotherapy. In addition, this study demonstrates that PEG-MnMOF@PTX can promote the maturation of dendritic cells and augment the infiltration of cytotoxic T lymphocytes through activation of the cyclic guanosine 5′-monophosphate–adenosine 5′-monophosphate synthase (cGAS) and interferon gene stimulator (STING) pathways, namely cGAS–STING pathways, thereby heightening the sensitivity to ICB immunotherapy. The findings of this study present a novel paradigm for the progress in cancer immunotherapy.
研究领域:
免疫疗法
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癌症生物学
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纳米技术
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药学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-18
·
IF 14.7
Su Zheng,Xu Dongdong,Hu Xianli,Zhu Wanbo,Kong Lingtong,Qian Zhengzheng,Mei Jiawei,Ma Ruixiang,Shang Xifu,Fan Wenpei,Zhu Chen
Pathogen-host competition for manganese and intricate immunostimulatory pathways severely attenuates the efficacy of antibacterial immunotherapy against biofilm infections associated with orthopaedic implants. Herein, we introduce a spatiotemporal sono-metalloimmunotherapy (SMIT) strategy aimed at efficient biofilm ablation by custom design of ingenious biomimetic metal-organic framework (PCN-224)-coated MnO 2 -hydrangea nanoparticles (MnPM) as a metalloantibiotic. Upon reaching the acidic H 2 O 2 -enriched biofilm microenvironment, MnPM can convert abundant H 2 O 2 into oxygen, which is conducive to significantly enhancing the efficacy of ultrasound (US)-triggered sonodynamic therapy (SDT), thereby exposing bacteria-associated antigens (BAAs). Moreover, MnPM disrupts bacterial homeostasis, further killing more bacteria. Then, the Mn ions released from the degraded MnO 2 can recharge immune cells to enhance the cGAS-STING signaling pathway sensing of BAAs, further boosting the immune response and suppressing biofilm growth via biofilm-specific T cell responses. Following US withdrawal, the sustained oxygenation promotes the survival and migration of fibroblasts, stimulates the expression of angiogenic growth factors and angiogenesis, and neutralizes excessive inflammation. Our findings highlight that MnPM may act as an immune costimulatory metalloantibiotic to regulate the cGAS-STING signaling pathway, presenting a promising alternative to antibiotics for orthopaedic biofilm infection treatment and pro-tissue repair.
研究领域:
生物医学工程
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材料科学
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免疫学
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骨科
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传染病
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
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IF 9.6
Heying Chen,Xiaomeng Cai,Jiayu Zhang,Hongyan Sun,Jie Zhang,Jun Chen,Zhenglin Yang,Dongqing Wang
Combination of chemotherapy and cancer immunotherapy has shown substantial clinical promise. However, the immunosuppressive tumor microenvironment (TME) poses a critical barrier to this combination therapy. Here, a tumor lysosome-targeted immunomodulatory strategy based on a biomimetic nanoadjuvant is presented, which effectively overcomes the immunosuppressive TME and demonstrates enhanced therapeutic efficacy when combined with chemotherapy. This nanoadjuvant integrates Fe-DOX coordination nanoparticles, a MnCO 3 shell, TLR7/8 agonist (R848), and a mature dendritic cell membrane (DCM) coating. The resulting DCM@(Fe-DOX-Mn-R848) nanoadjuvant induces immunogenic cell death in tumor cells via lysosomal-mitochondrial cascade destruction. Concurrently, it activates the cGAS-STING signaling pathway to promote dendritic cell maturation and repolarize tumor-associated macrophages from M2 to M1 phenotype, thereby effectively enhancing CD8 + T cell activation and tumor therapeutic efficacy. When combined with PD-L1 blockade therapy, the nanoadjuvant demonstrates enhanced efficacy in murine models of primary and recurrent triple-negative breast cancer, establishing durable immune memory. This platform demonstrates significant potential in overcoming immunosuppressive TME and advancing combination therapy through lysosome-targeting drug delivery technology, revealing promising prospects for cancer treatment.
研究领域:
纳米医学
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免疫学
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癌症生物学
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生物工程
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
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2024
·
IF 15.8
Weichong He,Wei Lv,Linfeng Liu,Yue Gong,Kefan Song,Jiangna Xu,Wei Zhao,Shengnan Li,Zhiyi Min,Qinhua Chen,Jiaqing Yin,Yuqin Chen,Hufeng Fang,Hongliang Xin,Xiangming Fang
Glioblastoma, the most prevalent malignant brain tumor, is a lethal threat to human health, with aggressive and infiltrative growth characteristics that compromise the clinical treatment. Herein, we developed a vitamin D3-inserted lipid hybrid neutrophil membrane biomimetic multimodal nanoplatform (designated as NED@MnO2-DOX) through doxorubicin (DOX)-loaded manganese dioxide nanoparticles (MnO2) which were coated with a vitamin D3-inserted lipid hybrid neutrophil membrane. It was demonstrated that in addition to chemotherapy and chemo-dynamic therapy efficacy, NED@MnO2-DOX exhibited great power to activate and amplify immune responses related to the cGAS STING pathway, bolstering the secretion of type I interferon-β and proinflammatory cytokines, promoting the maturation of DC cells and infiltration of CD8+T cells into the glioma tissue, thereby reversing the immunosuppressive microenvironment of glioma from a “cold” tumor to a “hot” tumor. The biomimetic multimodal nanoplatform has potential as a multimodal strategy for glioma-targeted treatment, especially holding considerable promise for the development of innate immune therapy for glioma.
研究领域:
肿瘤学
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纳米技术
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免疫治疗
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药学
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2022
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IF 16.874
Yuyue Zhao,Yuanwei Pan,Kelong Zou,Zhou Lan,Guowang Cheng,Qiuying Mai,Hao Cui,Qianfang Meng,Tongkai Chen,Lang Rao,Limin Ma,Guangtao Yu
The limited clinical response and serious side effect have been challenging in cancer immunotherapy resulting from immunosuppressive tumor microenvironment (TME) and inferior drug targeting. Herein, an active targeting TME nanoplatform capable of revising the immunosuppressive TME microenvironment is designed. Briefly, gold nanorods (GNRs) are covered with silica dioxide (SiO 2 ) and then coated manganese dioxide (MnO 2 ) to obtain [email protected] 2 @MnO 2 (GSM). Myeloid-derived suppressor cells (MDSCs) membrane is further camouflaged on the surface of GSM to obtain [email protected] 2 @MnO 2 @MDSCs (GSMM). In this system, GSMM inherits active targeting TME capacity of MDSCs. The localized surface plasmon resonance of GNRs is developed in near-infrared II window by MnO 2 layer coating, realizing NIR-II window photothermal imaging and photoacoustic imaging of GSMM. Based on the release of Mn 2+ in acidic TME, GSMM can be also used for magnetic resonance imaging. In cancer cells, Mn 2+ catalyzes H 2 O 2 into ·OH for (chemodynamic therapy) CDT leading to activate cGAS-STING, but also directly acts on STING inducing secretion of type I interferons, pro-inflammatory cytokines and chemokines. Additionally, photothermal therapy and CDT-mediated immunogenic cell death of tumor cells can further enhance anti-tumor immunity via exposure of CRT, HMGB1 and ATP. In summary, our nanoplatform realizes multimodal cancer imaging and dual immunotherapy.
研究领域:
纳米技术
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癌症免疫治疗
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医学成像
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诊疗一体化
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生物材料
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
·
IF 10.5
Xiuli Zhang,Mingjing Wei,Zhigang Zhang,Yarong Zeng,Feihong Zou,Sibo Zhang,Zhiping Wang,Fentian Chen,Hualong Xiong,Yufang Li,Lizhi Zhou,Tingting Li,Qingbing Zheng,Hai Yu,Jun Zhang,Ying Gu,Qinjian Zhao,Shaowei Li,Ningshao Xia
The cGAS-STING pathway and the Mevalonate Pathway are druggable targets for vaccine adjuvant discovery. Manganese (Mn) and bisphosphonates are known to exert adjuvant effects by targeting these two pathways, respectively. This study found the synergistic potential of the two pathways in enhancing immune response. Risedronate (Ris) significantly amplified the Mn adjuvant early antibody response by 166-fold and fortified its cellular immunity. However, direct combination of Mn 2+ and Ris resulted in increased adjuvant toxicity (40% mouse mortality). By the combination of doping property of hydroxyapatite (HA) and its high affinity for Ris, we designed Ris-functionalized Mn-HA micro-nanoparticles as an organic-inorganic hybrid adjuvant, named MnHARis. MnHARis alleviated adjuvant toxicity (100% vs. 60% survival rate) and exhibited good long-term stability. When formulated with the varicella-zoster virus glycoprotein E (gE) antigen, MnHARis triggered a 274.3-fold increase in IgG titers and a 61.3-fold surge in neutralization titers while maintaining a better long-term humoral immunity compared to the aluminum adjuvant. Its efficacy spanned other antigens, including ovalbumin, HPV18 VLP, and SARS-CoV-2 spike protein. Notably, the cellular immunity elicited by the group of gE + MnHARis was comparable to the renowned Shingrix®. Moreover, intratumoral co-administration with an anti-trophoblast cell surface antigen 2 nanobody revealed synergistic antitumor capabilities. These findings underscore the potential of MnHARis as a potent adjuvant for augmenting vaccine immune responses and improving cancer immunotherapy outcomes.
研究领域:
免疫学
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药学
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纳米技术
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病毒学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2022
·Vol. 32
·期 17
·2108883
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IF 19.924
Xiu Zhao,Kaixiang Zhang,Yiyang Wang,Wenxiao Jiang,Hui Cheng,Qiongwei Wang,Tingting Xiang,Zhenzhong Zhang,Junjie Liu,Jinjin Shi
Efficient nuclear DNA damage and release is highly recommended to improve the photodynamic immunotherapy by eliciting innate immune response yet remains challenging. Herein, an intracellular self-assembly driven nucleus-targeted photo-immune stimulator (PIS) with chromatin decompaction function is reported for innate and adaptive antitumor immunity co-activation. The PIS consists of vorinostat (SAHA)-loaded manganese-porphyrin metal-organic framework (Mn (III)-TCPP MOF) with further modification of AS1411 aptamer. The PIS can be efficiently internalized by tumor cells and disassembled under the intracellular overexpressed glutathione (GSH). Notably, the released AS1411 is able to be self-assembled with photosensitizer TCPP in situ within cells, driving nucleus-targeted delivery of TCPP; meanwhile, the loaded SAHA can induce chromatin decompaction, cooperatively promoting TCPP-mediated photodynamic nuclear DNA damage and cytosolic release under laser irradiation. In addition, the released manganese ions (Mn 2+ ) further enhance the cytosolic DNA/cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway mediated innate immunity, which synergizes with PDT-induced immunogenic cell death to achieve co-activation of innate and adaptive immunity. Compared to traditional PDT, the self-assembly driven nucleus-targeted PDT system with chromatin decompaction show significantly enhanced efficacy for inhibiting primary tumor growth and distant metastasis in several xenograft tumor models, mechanistically by promoting the maturation of dendritic cells and tumor infiltration of natural killer cell, cytotoxic T lymphocytes.
研究领域:
癌症研究
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免疫学
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药学
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纳米技术
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生物医学工程
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产品关联
DOI
高影响因子
BIOMATERIALS
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2023
·
IF 14
Lili Cheng,Peng Zhang,Yadong Liu,Zhuoyin Liu,Junjie Tang,Langtao Xu,Jie Liu
Due to the immunosuppressive tumor microenvironment (ITM) resulting from tumor-associated macrophages (TAMs) and regulatory T cells, immune checkpoint blockade and vaccine therapies often lead to an inadequate immune response. Recently, cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon gene (cGAS/STING)-mediated innate immunity has emerged as a promising cancer therapeutic, as STING pathway activation could promote dendritic cells (DCs) maturation and tumor-specific cytotoxic T lymphocyte (CTL) and natural killer (NK) cell infiltration. Herein, multifunctional hybrid exosomes for cGAS/STING activation are designed by fusing genetically engineered exosomes carrying CD47 derived from tumor cells with exosomes from M1 macrophages, which are further encapsulated with DNA-targeting agent (SN38) and STING-agonist (MnO 2 ). The hybrid exosomes demonstrate great tumor-targeting capacity and prolong blood circulation time due to the surface decoration of CD47. At the tumor site, the hybrid exosomes induce TAMs polarization to the M1 phenotype and release SN38 to induce DNA damage and Mn 2+ to stimulate cGAS/STING activation. Furthermore, the resulting multifunctional hybrid exosomes (SN/Mn@gHE) promote DCs maturation and facilitate CTL infiltration and NK cell recruitment to the tumor region, leading to significant anti-tumor and antimetastatic efficacy. Our study suggests a novel strategy to enhance cancer immunotherapy by activating the STING pathway and ameliorating ITM.
研究领域:
癌症生物学
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免疫学
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药学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Ying Luo,Zhongsheng Xu,Qianying Du,Lian Xu,Yi Wang,Jie Xu,Junrui Wang,Sijin Chen,Wenli Zhang,Bo Liu,Jia Liu,Dajing Guo,Yun Liu
The immune landscape of late-stage liver cancer is featured by severe immunosuppression that is characterized by poor immunogenicity, T-cell exhaustion, and infiltration of a large number of immunosuppressive cells, leading to compromised therapeutic efficacy of mainstream immunotherapies. Herein, we developed a pleiotropic immune cell mobilization strategy to modulate immune systems for immunosuppressive liver cancer therapy. In this study, immunogenic bacteria-derived outer membrane vesicles (OMVs) were exploited as a vector to deposit Cu and Mn with mixed valence states via one-step biomineralization, followed by platelet membrane camouflage, which are denoted as OPCM. Mechanistically, the pleiotropic OPCM possesses POD, CAT, and GPX-like activities, thereby achieving cGAS-STING activation, immunogenic ferroptosis, and tumor hypoxia alleviation, ultimately leading to initiation of the cancer immunity cycle, modulation of both innate and adaptive immune system, and reversion of immunosuppression. Notably, the combination with typical αPD-L1 treatment augmented the tumor suppression effect by amplifying the intensity of ferroptosis due to IFN-γ secretion by activated T cells. Overall, the metal biomineralized OPCMs in combination with αPD-L1 formed a closed-loop therapy that cycles from immunotherapy and ferroptosis therapy, providing new insights for treating immunosuppressive liver cancer.
研究领域:
免疫学
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癌症生物学
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生物技术
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纳米医学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）