ADVANCED MATERIALS
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2025
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IF 26.8
Xiaoya Guo,Zhiyu Yang,Zhaopei Guo,Huiyan Lai,Hanyu Meng,Meng Meng,Tong Li,Zhen Li,Jie Chen,Yuanji Feng,Xuan Pang,Huayu Tian,Xuesi Chen
The development of mRNA delivery carriers with innate immune stimulation functions has emerged as a focal point in the field of mRNA vaccines. Nonetheless, the expression of mRNA in specific sites and innate immune stimulation at specific sites are prerequisites for ensuring the safety of mRNA vaccines. Based on the synthetic PEIRs carriers library, this study identifies an innovative mRNA delivery carrier named POctS with the following characteristics: 1) simultaneously possessing high mRNA delivery efficiency and stimulator of interferon genes (STING) stimulation function. 2) Leveraging the distinctive site-specific delivery capabilities of POctS, the expression of mRNA at specific sites and the activation of innate immune responses at designated sites are achieved, minimizing formulation toxicity and maximizing the vaccine performance. 3) Tailoring two types of mRNA vaccines based on POctS according to the immune infiltration status of different types of tumors. Briefly, POctS-loading ovalbumin (OVA) mRNA as a tumor antigen vaccine achieves the prevention and treatment of melanoma in mice. Further, POctS-loading mixed lineage kinase domain-like protein (MLKL) mRNA as an in situ tumor vaccine effectively treats orthotopic pancreatic cancer in mice. This delivery carrier offers a feasible mRNA vaccine-based immunotherapy strategy for various types of tumors.
研究领域:
分子生物学
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免疫学
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肿瘤学
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DOI
PubMed
高影响因子
MOLECULES
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2023
·Vol. 28
·期 9
·3740
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IF 4.6
Jibing Zhang,Xiao Cui,Yujiao Huang,Xiangdong Xu,Changshun Feng,Jun Li
Breast cancer is one of the most common cancers worldwide, posing a serious threat to human health. Recently, innate immunity has become a widely discussed topic in antitumor research. The STING pathway is an important component of innate immunity, and several STING agonists have been developed and applied in antitumor research. Dimeric amidobenzimidazole (diABZI) is one STING agonist and is a nucleotide analog with low serological stability and cell membrane permeability. In this study, we prepared diABZI-encapsulated liposomes (dLNPs) using the ammonium sulfate gradient method. The average particle size of the dLNPs was 99.76 ± 0.230 nm, and the encapsulation efficiency was 58.29 ± 0.53%. Additionally, in vivo and in vitro assays showed that the dLNPs had a sustained-release effect and that the circulation time in vivo was longer than 48 h. The expression of IFN-β and IFN-γ was elevated in mice treated with dLNPs. Moreover, we found that dLNPs can recruit CD8+T cells to tumor tissue and exert antitumor effects. The dLNPs-treated group showed the most significant efficacy: the average tumor volume was 231.46 mm3, which decreased by 78.16% and 54.47% compared to the PBS group and diABZI group. Meanwhile, the hemolysis rate of the dLNPs was 2%, showing high biocompatibility. In conclusion, dLNPs can effectively suppress tumor growth and possess great potential in breast cancer therapy.Keywords:STING;agonist;liposomes;antitumor;breast cancer
研究领域:
肿瘤学
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免疫疗法
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药学
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DOI
PubMed
高影响因子
BIOMATERIALS
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2025
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IF 12.9
Siying Wen,Xuemin He,Jiachen Wang,Zheyao Wen,Heying Ai,Mengyin Cai,Yi Yang,Hejun Li,Shasha Li,Guojun Shi,Aimin Xu,Zecong Xiao,Xintao Shuai,Yanming Chen
Retinal neovascularization is the main pathologic feature of ischemic retinopathy, which eventually leads to vision loss and even blindness. Current treatments like laser photocoagulation and intravitreal injection of anti-vascular endothelial growth factor A (VEGFA) drugs are invasive, expensive, and incompetent. Therefore, it is urgent to explore optimized therapies, particularly eye drops, to improve treatment effects. Our recent study reported that abnormal activation of the stimulator of interferon genes (STING) is closely associated with retinal vascular diseases, and it is highly enriched in retinal endothelial cells (ECs) with retinopathy. Thus, we evaluated whether endothelial STING affects retinal neovascularization. In addition, we constructed iRGD- and TAT-decorated nanoparticles (NPs) loaded with C-176 (I/T-C-NP), capable of penetrating the cornea and targeting retinal ECs. The I/T-C-NP eye drops were applied to the eyes of oxygen-induced retinopathy (OIR) mice, resulting in attenuated activation of the STING pathway. Consequently, retinal neovascularization and vascular tortuosity were effectively reduced, astrocyte activation was prohibited, and pericyte coverage was improved. These observations suggest that I/T-C-NP eye drops can be a potential solution for the treatment of retinal neovascularization.
研究领域:
眼科
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分子生物学
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药物递送
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Yushun Chang,Jie Lin,Bo Yang,Yuxuan Shen,Weijun Zhao,Hao Shen,Quan Yang,Haowen Lu,Xiujun Cai,Yifan Wang,Wen Hua
Background Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, exhibits anticancer activity in several malignancies, but its efficacy and mechanisms in gallbladder cancer (GBC) remain undefined. Methods Human GBC cell lines (GBCs) were treated with ALO and assessed for viability, colony formation, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation and apoptosis. Autophagic flux and related signaling were evaluated by western blotting and immunofluorescence. In vivo antitumor activity was determined in a nude mouse xenograft model. Results ALO markedly inhibited the proliferation ability of GBCs and disrupted autophagosome–lysosome fusion, leading to reactive oxygen species (ROS) accumulation and apoptosis. Furthermore, ALO induced DNA damage and nuclear release of double-stranded DNA (dsDNA) to cytoplasm, leading to cyclic-GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-mediated interferon (IFN) pathway activation and enhancing natural killer cells (NK cells) activation in vitro. In vivo, ALO reduced subcutaneous GBCs xenograft volume and weight and, along with increased cleaved caspase-3 and BAX expression in tumor tissues, confirming tumor cell apoptosis. Conclusions These findings indicate that ALO may serve as a novel therapeutic candidate for gallbladder cancer by inhibiting autophagic flux to induce ROS-mediated apoptosis while activating the cGAS–STING–IFN pathway to enhance antitumor immunity.
研究领域:
肿瘤学
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分子生物学
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药理学
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免疫学
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转化医学
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细胞信号转导
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DOI
PubMed
高影响因子
BIOMATERIALS
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2025
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IF 12.9
Lirui Jia,Yang Qin,Xin Li,Hongzhuo Liu,Zhonggui He,Yongjun Wang
Cancer vaccines represent a promising therapeutic strategy in oncology, yet their effectiveness is often hampered by suboptimal antigen targeting, insufficient induction of cellular immunity, and the immunosuppressive tumor microenvironment. Advanced delivery systems and potent adjuvants are needed to address these challenges, though a restricted range of adjuvants for human vaccines that are approved, and even fewer are capable of stimulating robust cellular immune response. In this work, we engineered a unique self-adjuvanted platform (MLDHs) by integrating STING agonists manganese into a layered double hydroxide nano-scaffold, encapsulating the model antigen ovalbumin (OVA). The MLDHs platform encompasses Mn-doped MgAl-LDH (MLMA) and Mn-doped MgFe-LDH (MLMF). Upon subcutaneous injection, OVA/MLDHs specifically accumulated within lymph nodes (LNs), where they were internalized by resident antigen-presenting cells. The endosomal degradation of MLDHs facilitated the cytoplasmic release of antigen and Mn 2+ , promoting cross-presentation and triggering the STING pathway, which in turn induced a potent cellular immune response against tumors. Notably, OVA/MLMF induced stronger M1 macrophage polarization and a more potent T-cell response within tumor-infiltrating lymphocytes compared to OVA/MLMA, leading to significant tumor regression in B16F10-OVA bearing mice with minimal adverse effects. Additionally, combining MLMF with the vascular disrupting agent Vadimezan disrupted the tumor's central region, typically resistant to immune cell infiltration, further extending survival in tumor-bearing mice. This innovative strategy may show great potential for improving cancer immunotherapy and offers hope for more effective treatments in the future.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
IMMUNITY
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2021
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IF 31.745
Run Fang,Qifei Jiang,Yukun Guan,Pengfei Gao,Rui Zhang,Zhen Zhao,Zhengfan Jiang
Summary Activation of the cyclic guanosine monophosphate (GMP)-AMP (cGAMP) sensor STING requires its translocation from the endoplasmic reticulum to the Golgi apparatus and subsequent polymerization. Using a genome-wide CRISPR-Cas9 screen to define factors critical for STING activation in cells, we identified proteins critical for biosynthesis of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus. Binding of sGAGs promoted STING polymerization through luminal, positively charged, polar residues. These residues are evolutionarily conserved, and selective mutation of specific residues inhibited STING activation. Purified or chemically synthesized sGAGs induced STING polymerization and activation of the kinase TBK1. The chain length and O -linked sulfation of sGAGs directly affected the level of STING polymerization and, therefore, its activation. Reducing the expression of Slc35b2 to inhibit GAG sulfation in mice impaired responses to vaccinia virus infection. Thus, sGAGs in the Golgi apparatus are necessary and sufficient to drive STING polymerization, providing a mechanistic understanding of the requirement for endoplasmic reticulum (ER)-to-Golgi apparatus translocation for STING activation.
研究领域:
免疫学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Nano Today
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2025
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IF 10.9
Zhaochu Xu,Jiang Yu,Yingxi Zhang,Yue Wang,Wenxiao Li,Baoyue Zhang,Wenwen Cui,Yicheng Li,Yue Wang,Zimeng Yang,Yubo Liu,Xin Li,Yongjun Wang,Zhonggui He,Hongzhuo Liu
Cancer vaccine has emerged as a promising therapeutic paradigm for cancer therapy. However, the lack of tumor-associated antigens and abundant immunosuppressive factors seriously diminish the efficacy of immunotherapy, resulting in poor clinical benefits. In this report, we engineered a coordinated immunostimulatory nanoplatform, termed MP@PPS NPs, by physically combining reactive oxygen species (ROS)-responsive poly (propylene sulfide) nanoparticles loaded with the photosensitizer pyropheophorbide a (PPa) and stimulator of interferon genes (STING) agonist (MSA-2), to function as an in situ cancer vaccine to amplify immunotherapeutic outcomes. Excellent stability of MP@PPS NPs endowed prolonged drug circulation time and improved tumor accumulation, while their small size boosted deeper drug penetration within tumors. Crucially, upon laser irradiation, the MP@PPS NPs could generate abundant ROS, which induced tumor ablation, triggered immunogenic cell death to initiate an adaptive antitumor immune response and facilitated the local release of MSA-2, thereby promoting innate antitumor immunity through the cGAS-STING pathway. MP@PPS NPs markedly suppressed both primary and distant tumor progression, promoted dendritic cell maturation and increased cytotoxic T lymphocyte infiltration, elicited robust antitumor immunity. Meanwhile, MP@PPS NPs treatment impeded the lung metastatic in conjunction with anti-PD-L1 treatment. This work holds significant promise for the synergistic photodynamic immunotherapy, and offers a crucial inspiration for addressing the problems of insufficient antitumor immunity and ineffective cancer treatments.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
高影响因子
ADVANCED MATERIALS
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2025
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IF 26.8
Nailin Yang,Shumin Sun,Jiachen Xu,Fei Gong,Huali Lei,Yu Hao,Zifan Pei,Chenya Wang,Qiao Yu,Jihu Nie,Nan Jiang,Caifang Ni,Liang Cheng
The cGAS-STING pathway is pivotal in initiating antitumor immunity. However, tumor metabolism, particularly glycolysis, negatively regulates the activation of the cGAS-STING pathway. Herein, Mn galvanic cells (MnG) are prepared via liquid-phase exfoliation and in situ galvanic replacement to modulate tumor metabolism, thereby enhancing cGAS-STING activation for bidirectional synergistic H 2 -immunotherapy. The obtained MnG can be etched by water, enabling efficient and sustained generation of H 2 gas and Mn 2+ . MnG not only activated and amplified the cGAS-STING pathway through the sustained release of Mn 2+ but also regulated tumor glucose metabolism to inhibit the expression of three prime repair exonuclease 2 (TREX2), thereby synergistically enhancing the activation of the cGAS-STING pathway. The injection of MnG into tumors resulted in a robust immune response, thereby providing favorable support for antitumor therapy. Consequently, the combination of MnG with immune checkpoint blockade therapy resulted in significant suppression of both primary tumors and distant tumors. Furthermore, the MnG-lipiodol dispersion exhibited remarkable efficacy in combination with transarterial embolization (TAE)-gas-immunotherapy in a rabbit orthotopic liver tumor model. The present study underscores the significance of employing a metal galvanic cell strategy for enhanced immunotherapy, thereby offering a novel approach for rational design of bioactive materials to augment immunotherapeutic effectiveness.
研究领域:
肿瘤学
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免疫学
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生物化学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Fuming Wang,Xiaodong Zhu,Qianwen Zhang,Minghui Xie,Lei He,Jiahao Guo,Ang Li,Qingsong Yang,Jijin Yang,Wei Li
Cryoablation (CRA) is a clinical treatment modality for minimally invasive local tumor ablation. Rare clinical reports have shown that CRA can induce a cryoimmune effect and enhance systemic anti-tumor immunity against potential metastases, a phenomenon known as the “abscopal effect”. Here, we innovatively propose a sequential treatment strategy to improve the tumor immune microenvironment by activating the cGAS-STING signaling pathway of immune cells and mild photothermal therapy (mPTT) before CRA, making this rare but exciting phenomenon more reproducible. Specifically, we designed functional nanosheets (Ti 3 C 2 @Au-PEG-DMXAA) based on Ti 3 C 2 MXene, with gold nanoparticles attached to the surface, PEGylated, and loaded with the STING agonist (DMXAA). Due to the attachment of gold nanoparticles, CT-guided visual injection of the functional nanosheets was achieved. The synergistic effect of mPTT and STING pathway activation promoted the immunogenic death of tumor cells, activation of dendritic cells, repolarization of tumor-associated macrophages, and enrichment of cytotoxic T cells in the tumor microenvironment. Subsequently, sequential CRA eradicated local “hot” tumors, initiating a “cancer vaccines” effect through the in-situ gradual release of tumor-associated antigens, boosting systemic anti-tumor immunity, and effectively generating long-term immune memory, thereby inhibiting tumor recurrence and distant metastases.
研究领域:
肿瘤学
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纳米医学
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免疫学
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产品关联
DOI
高影响因子
ACS Nano
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2025
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IF 16
Yaping Wu,Pengfei Diao,Yayun Peng,Yuhan Yang,Yuhan Wang,Pin Lv,Jin Li,Dongmiao Wang,Ting Cai,Jie Cheng
Current immunotherapies such as immune checkpoint blockades (ICBs) have revolutionized oncotherapy regime; however, their responsiveness and efficiencies among patients with head and neck squamous cell carcinoma (HNSCC) remain quite limited. The existence of therapeutic-refractory cancer stem cells (CSCs) and inadequate activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway greatly contribute to immune evasion and immunotherapeutic resistance. Herein, we sought to develop a nanocomplex for HNSCC therapy by simultaneous CSCs eradication and STING activation. PTC209/MnO2@BSA (bovine serum albumin) nanoparticles (PMB NPs) synthesized via a facile and green process are reported, wherein the released manganese (Mn) ions under acidic tumor microenvironment significantly enhance cGAS-STING signals and facilitate the dendritic cells maturation to unleash the T-cell-mediated immune response. Meanwhile, PTC209 released from PMB NPs targets BMI1+ CSCs to suppress cancer stemness and epithelial-mesenchymal transition (EMT) and elicits apoptosis to further potentiate Mn-based metalloimmunotherapy. Both in vitro and in vivo experiments elucidate that PMB NPs function as designed, exerting powerful immunotherapeutic and chemotherapeutic impacts to impede HNSCC growth and metastasis as well as bolster anti-PD-1-based ICB. Collectively, our findings provide a promising therapeutic strategy against HNSCC by combinational CSCs elimination and STING activation via metalloimmunotherapy.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
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2023
·Vol. 14
·期 1
·1-12
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IF 16.6
Jia Mutian,Wang Yuanyuan,Wang Jie,Qin Danhui,Wang Mengge,Chai Li,Fu Yue,Zhao Chunyuan,Gao Chengjiang,Jia Jihui,Zhao Wei
Stimulator of interferon gene (STING)-triggered autophagy is crucial for the host to eliminate invading pathogens and serves as a self-limiting mechanism of STING-induced interferon (IFN) responses. Thus, the mechanisms that ensure the beneficial effects of STING activation are of particular importance. Herein, we show that myristic acid, a type of long-chain saturated fatty acid (SFA), specifically attenuates cGAS-STING-induced IFN responses in macrophages, while enhancing STING-dependent autophagy. Myristic acid inhibits HSV-1 infection-induced innate antiviral immune responses and promotes HSV-1 replication in mice in vivo. Mechanistically, myristic acid enhances N-myristoylation of ARF1, a master regulator that controls STING membrane trafficking. Consequently, myristic acid facilitates STING activation-triggered autophagy degradation of the STING complex. Thus, our work identifies myristic acid as a metabolic checkpoint that contributes to immune homeostasis by balancing STING-dependent autophagy and IFN responses. This suggests that myristic acid and N-myristoylation are promising targets for the treatment of diseases caused by aberrant STING activation.
研究领域:
免疫学
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细胞生物学
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病毒学
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代谢
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2025
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IF 12.9
Nasha Qiu,Chang Xu,Zhen Zhang,Rui Wang,Xuyong Wei,Yangla Xie,Shuai Wang,Di Lu,Kai Wang,Shengjun Xu,Chenchen Shen,Renyi Su,Beini Cen,Yanpeng Liu,Youqing Shen,Xiao Xu
Effective cancer immune therapy requires the orchestration of antigen induction, presentation and T-cell activation, further enhanced by anti-angiogenesis treatment; therefore, multiple therapeutics are generally used for such combination therapy. Herein, we report esterase-hydrolysable cationic polymers, N -[3-((4-acetoxy benzyl) oxy)-3-oxopropyl]- N -methyl-quaternized PEI (ERP) and poly{ N -[2-(acryloyl-oxy) ethyl]- N -[p-acetyloxyphenyl]- N,N -dimethylammonium chloride} (PQDMA), capable of simultaneously inducing tumor cell immunogenic cell death (ICD) to release antigens, activating the cGAS-STING pathways of tumor macrophages and dendritic cells, and releasing antiangiogenic agent p -hydroxybenzyl alcohol (HBA). Thus, intratumoral injection of ERP or PQDMA systemically boosted the anti-cancer immunities and inhibited tumor angiogenesis in mouse hepatocellular carcinoma and melanoma bilateral tumor models, leading to more effective tumor growth inhibition of both treated and abscopal untreated tumors than ICD alone induced by mitoxantrone and control cationic polymers. The mechanism study of gene knockout mice and transcriptome sequencing analysis confirmed the involvement of cGAS-STING and type I IFN signaling pathways. This work demonstrates ERP and PQDMA as the first examples of inherent therapeutic polymers, accomplishing systemic tumor inhibition without combining other therapeutic agents.
研究领域:
生物医学工程
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免疫学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
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