JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-21
·
IF 12.6
Ma Shanshan,Zhang Xuequan,Zhu Xiaoqi,Yan Kangning,Wang Qin,Lei Lei,Li Jiasheng,Guo Jing,Tang Weizhong,Liu Junjie,Cao Jun,Wang Duo,Luo Tao
Manganese ions (Mn 2+ ) have emerged as promising activators of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, their clinical application was hindered by low bioavailability and limited immune activation pathways, which impaired their ability to trigger robust immune responses and achieve significant antitumor effects. To address these challenges, we developed a dual-modality immune nano-activator by coordinating manganese ions with quercetin. This strategy was designed to enhance the cGAS-STING pathway activation and elicit the immunogenic cell death, thereby strengthening the antitumor immune response. The engineered nano-activator demonstrated superior tumor-targeting ability and efficient cellular internalization. Upon exposure to near-infrared irradiation, the system harnessed photothermal effects to induce apoptosis in tumor cells while simultaneously accelerating the release of manganese ions and quercetin. The released manganese ions facilitated the generation of reactive oxygen species, which in conjunction with quercetin-induced apoptosis, amplified photothermal-induced DNA damage. This DNA damage further promoted the release of cytosolic DNA, which in turn activated the cGAS-STING pathway, thereby intensifying immune activation. Notably, the nano-activator also triggered immunogenic cell death, which synergized with the cGAS-STING activation to promote dendritic cell maturation and activate antigen-specific T-cell, significantly enhancing the immune response against the tumor. Both in vitro and in vivo studies confirmed that this nano-activator effectively inhibited tumor growth, with particularly pronounced effects when combined with anti-CTLA-4 antibodies. Graphical abstract
研究领域:
纳米医学
·
肿瘤免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Nan Zhong,Ziyue Zu,Yishi Lu,Xuan Sha,Yang Li,Yang Liu,Shangyu Lu,Xi Luo,Yan Zhou,Jun Tao,Feiyun Wu,Zhaogang Teng,Yuxia Tang,Shouju Wang
Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway could effectively initiate antitumor immunity in triple-negative breast cancer. However, current nuclear DNA-mediated activation of STING pathway remains constrained by the tight protection of nuclear membrane and histones, highlighting the need for new strategies to enhance its efficacy. Mitochondrial DNA (mtDNA), in contrast, is more vulnerable to damage. Herein, our nanoplatforms exploited the high glutathione (GSH) environment characteristic of tumors to release abundant Mn 2+ , which induced mitochondrial dysfunction and the release of endogenous mtDNA. The released mtDNA, in conjunction with Mn 2+ itself functioning as a strong cGAS agonist, effectively activated cGAS-STING pathway. Consequently, the cGAS-STING-dependent secretion of type I interferon successively enhanced the maturation of dendritic cells and cross-priming of CD8 + T cells. In a poorly immunogenic 4T1 tumor model, TPP-MMONs efficiently primed systemic antitumor immunity and significantly enhanced the therapeutic efficacy of αPD-L1 therapy, suppressing tumor growth in both localized and metastatic tumor models. These findings provided an innovative and straightforward strategy to enhance TNBC immunogenicity by targeting mitochondrial damage to induce mtDNA-mediated cGAS-STING activation, thereby sensitizing tumors to immune checkpoint inhibitor therapy. Statement of Significance The cGAS-STING pathway is a promising target for overcoming immunoresistance in TNBC. However, current nuclear DNA-based activation strategies are limited by the tight protection of nuclear membrane and histones. Herein, we reported novel manganese-rich, mitochondria-targeting nanoplatforms (TPP-MMONs), which can release abundant Mn²⁺ and significantly induce mitochondrial dysfunction, leading to the release of mtDNA. As a result, the nanoplatforms can effectively stimulate the cGAS-STING pathway, thereby enhancing immune responses and improving the therapeutic efficacy of αPD-L1 therapy, offering new insights into TNBC treatments.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·
IF 12.6
Xinyao Hu,Hua Zhu,Yang Shen,Lang Rao,Jiayi Li,Xiaoqin He,Ximing Xu
Tumor immunotherapy aims to harness the immune system to identify and eliminate cancer cells. However, its full potential is hindered by the immunosuppressive nature of tumors. Radiotherapy remains a key treatment modality for local tumor control and immunomodulation within the tumor microenvironment. Yet, the efficacy of radiotherapy is often limited by tumor radiosensitivity, and traditional radiosensitizers have shown limited effectiveness in hepatocellular carcinoma (HCC). To address these challenges, we developed a novel multifunctional nanoparticle system, ZIF-8@MnCO@DOX (ZMD), designed to enhance drug delivery to tumor tissues. In the tumor microenvironment, Zn²⁺ and Mn²⁺ ions released from ZMD participate in a Fenton-like reaction, generating reactive oxygen species (ROS) that promote tumor cell death and improve radiosensitivity. Additionally, the release of doxorubicin (DOX)-an anthracycline chemotherapeutic agent-induces DNA damage and apoptosis in cancer cells. The combined action of metal ions and double-stranded DNA (dsDNA) from damaged tumor cells synergistically activates the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, thereby initiating a robust anti-tumor immune response. Both in vitro and in vivo experiments demonstrated that ZMD effectively activates the cGAS-STING pathway, promotes anti-tumor immune responses, and exerts a potent tumor-killing effect in combination with radiotherapy, leading to regression of both primary tumors and distant metastases. Our work provides a straightforward, safe, and effective strategy for combining immunotherapy with radiotherapy to treat advanced cancer.
研究领域:
肿瘤学
·
免疫学
·
放射生物学
·
纳米医学
✓ 已验证
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
·
免疫学
·
纳米技术
·
风湿病学
✓ 已验证
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
·
免疫学
·
纳米技术
✓ 已验证
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
·
癌症生物学
·
纳米技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yinglin Zhou,Xinchang Huang,Dezhou Wu,Xiaomei Xie,Hechun Li,Qi Wang,Yan Liao,Huanan Li
High-intensity focused ultrasound (HIFU) represents a game-changing breast-conserving treatment, with its induced immune response playing a crucial role in prognosis. However, the low immunogenicity and immunosuppressive microenvironment of tumors after surgery have prevented HIFU from generating strong antitumor immune responses, resulting in tumor recurrence and metastasis. Herein, we developed CaCO 3 -loaded metal–organic frameworks (MOFs) comprising Mn 2+ , hypoxia-activated prodrug banoxantrone (AQ4N), and stimulator of interferon genes (STING) agonist SR-717 to enhance HIFU-induced antitumor immunotherapy. Upon effective accumulation and drug release within tumor microenvironment (TME), MOFs exploit HIFU-exacerbated hypoxia to activate AQ4N, thereby inducing immunogenic cell death and enhancing tumor immunogenicity. Meanwhile, Mn 2+ enhances the activity of SR-717, synergistically amplifying STING activation and effectively promoting immune cell infiltration. Moreover, CaCO 3 complements immunotherapy by depleting lactate in TME, remodeling the immune microenvironment. As a result, MOFs enhance HIFU postoperative antitumor immune responses, significantly inhibiting tumor recurrence and metastasis. This work provides valuable insights to improve the prognosis of all surgical procedures, including HIFU.
研究领域:
肿瘤学
·
免疫学
·
生物医学工程
·
药学
✓ 已验证
产品关联
DOI
高影响因子
Small
·
2025
·
IF 12.1
Jiaojiao Tao,Yu Dong,Bingjie Wang,Teng Wang,Aijia Zhang,Shuang Li,Rui Chen,Yanguo Su,Tianze Jiang,Xia Zhao
Immunotherapy is a promising new approach for tumor treatment. However, its clinical application is hindered by insufficient immunogenicity, hypoxia, and immunosuppressive tumor microenvironment (TME). Here, oxygen pump microneedles (OPMNs) loaded with zinc-doped copper sulfide nanoflowers (ZCS NFs) and PD-L1 small interfering RNA (siPD-L1) (OPMNs-ZCS@siPD-L1) are developed for boosting tumor immunotherapy. OPMN-ZCS@siPD-L1 enhances tumor immunogenicity through ZCS NFs by inducing cuproptosis, reverses TME through siPD-L1, and promotes drug penetration, and ameliorates hypoxia through oxygen bubbles. More importantly, cuproptosis-induced mitochondrial DNA (mtDNA) together with Zn 2+ co-activate the STING pathway, triggering a robust immune response. OPMN-ZCS@siPD-L1 increases the sensitivity to cuproptosis and induces immunogenic cell death (ICD) in vivo and in vitro, which significantly inhibits tumor progression and metastasis. The novel strategy of “increasing the throttle” (cuproptopsis-mediated STING activation & ICD effect) combined with “releasing the brake” (PD-L1 inhibition & hypoxia improvement) provides a new approach for enhancing percutaneous tumor immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2022
·Vol. 9
·期 32
·2203523
·
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.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Xinchang Huang,Hechun Li,Qi Wang,Yan Liao,Xiaomei Xie,Yinglin Zhou,Dezhou Wu,Huanan Li
High-intensity focused ultrasound (HIFU) has great potential as a noninvasive, breast-conserving treatment for patients with breast cancer. The HIFU-induced antitumor immune response plays a critical role in postoperative prognosis. However, after surgery, tumor cells exhibit low immunogenicity, and severe hypoxia exacerbates the immunosuppressive tumor microenvironment, thereby rendering HIFU-induced immune effects insufficient to prevent tumor recurrence and metastasis. Herein, hypoxia-responsive, crosslinked albumin-based nanoparticles (HACS NPs), comprising the hypoxia-activated prodrug AQ4N, the stimulator of interferon genes (STING) agonist SR-717, and calcium carbonate (CaCO 3 ), were developed to augment the postoperative antitumor immune response. The HACS NPs are activated to “on” state in the postoperative hypoxic tumor microenvironment and release the loaded AQ4N to increase immunogenic cell death (ICD). Moreover, SR-717 promotes intratumoral infiltration of immune cells through STING activation, while CaCO 3 creates immune-supportive tumor microenvironment by consuming lactate, thereby polarizing M2 macrophages to the M1 phenotype. Based on these improvements, the HACS NPs have been shown to significantly enhance the post-HIFU antitumor immune response, effectively suppress tumor recurrence and metastasis. This work provides a successful paradigm for improving the prognosis of surgical interventions, including HIFU.
研究领域:
肿瘤学
·
生物医学工程
·
免疫学
✓ 已验证
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
·
生物材料学
✓ 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）