Advanced Healthcare Materials
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2023
·
IF 10
Ping Ji,Xin-Chen Deng,Xiao-Kang Jin,Shi-Man Zhang,Jia-Wei Wang,Jun Feng,Wei-Hai Chen,Xian-Zheng Zhang
Tumor immunotherapy is commonly hindered by inefficient delivery and presentation of tumor antigens as well as immunosuppressive tumor microenvironment. To overcome these barriers, a tumor-specific nanovaccine capable of delivering tumor antigens and adjuvants to antigen-presenting cells and modulating the immune microenvironment to elicit strong antitumor immunity is reported. This nanovaccine, named FCM@4RM, is designed by coating the nanocore (FCM) with a bioreconstituted cytomembrane (4RM). The 4RM, which is derived from fused cells of tumorous 4T1 cells and RAW264.7 macrophages, enables effective antigen presentation and stimulation of effector T cells. FCM is self-assembled from Fe(II), unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG), and metformin (MET). CpG, as the stimulator of toll-like receptor 9, induces the production of pro-inflammatory cytokine and the maturation of cytotoxic T lymphocytes (CTLs), thereby enhancing antitumor immunity. Meanwhile, MET functions as the programmed cell death ligand 1 inhibitor and can restore the immune responses of T cells against tumor cells. Therefore, FCM@4RM exhibits high targeting capabilities toward homologous tumors that develop from 4T1 cells. This work offers a paradigm for developing a nanovaccine that systematically regulates multiple immune-related processes to achieve optimal antitumor immunotherapy.
研究领域:
癌症免疫学
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纳米技术
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药学
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免疫治疗
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DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2026
·Vol. 83
·期 1
·76
·
IF 6.2
Feiyu Lu,Shengnan Wang,Mengru Zhu,Kuo Qu,Tong Zhu,Hong Wang,Yongli Yu,Liying Wang
The imbalanced expression of interferon regulatory factor (IRF) 4 and IRF8 in activated B cells significantly influences their differentiation and promotes the development of immune-related diseases. Restoring abnormal B cells to appropriate responses may treat these diseases. In this study, an oligodeoxynucleotide (ODN) S2, designed according to the consensus sequence recognized by IRFs in interferon-stimulated response elements, was used as an immunomodulator to investigate its effects on mouse splenic B cells stimulated with the TLR9 agonist CpG ODN, either alone or in combination with antigen, and to explore its underlying mechanisms. The results showed that S2 had a significant negative regulatory effect on CpG ODN induced B cell activation. It also significantly downregulated the production of IL-6 and the percentage of IL-6 + B cells in splenocytes stimulated by CpG ODN, but significantly upregulated the percentage of IL-10 + B cells. Interestingly, S2 impaired antibody production both in vitro and in vivo, but rescued mice from lethal inflammatory responses. Further studies showed that S2 could bind IRF4 and IRF8 with high affinity, slightly upregulate phosphorylated IRF4, reduce the expression and nuclear translocation of IRF8, and alter the proportion of IRF4 + , IRF8 + or double-positive B cells in spleen cells induced by CpG ODN. These results suggest that S2 acts as a decoy directing some B cells to differentiate into IL-10-producing Breg-like cells rather than plasma cells by restoring the TLR9 signal-induced IRF4 and IRF8 ratio imbalance. This indicates its potential as an immunomodulator for the treatment of diseases associated with B-cell abnormalities.
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DOI
PubMed
高影响因子
Nanoscale
·
2019
·Vol. 11
·期 42
·19912-19922
·
IF 6.97
Dongsheng Zhang,Ping Cui,Zhichao Dai,Baochan Yang,Xiuxiu Yao,Qingyun Liu,Zunfu Hu,Xiuwen Zheng
The metastasis and recurrence of tumors are the main reasons for cancer death. In this work, a promising therapy for tumor treatment that can eliminate primary tumors and prevent tumor relapses is introduced by combining chemotherapy, photothermal therapy (PTT) and immunotherapy. Multifunctional FePt/MoS2-FA nanocomposites (FPMF NCs) were obtained via anchoring FePt nanoparticles and folic acid (FA) on MoS2 nanosheets. As an efficient ferroptosis agent, FePt nanoparticles could catalyze the Fenton reaction to produce the reactive oxygen species (ROS). Through the highly effective photothermal conversion of MoS2 nanosheets, the primary tumor cells could be ablated by photothermal therapy (PTT). Moreover, the metastatic tumors were eliminated effectively with the help of oligodeoxynucleotides containing cytosine–guanine (CpG ODNs) combined with systemic checkpoint blockade therapy using an anti-CTLA4 antibody. Even more intriguingly, a strong immunological memory effect was obtained by this synergistic therapy. Taking all these results into consideration, we anticipate that the photo-chemo-immunotherapy strategies show great promise toward the development of a multifunctional platform for anticancer therapeutic applications.
研究领域:
肿瘤学
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纳米技术
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免疫疗法
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材料科学
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治疗学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Zhuoya Gao,Jiarong Zhang,Yingchao Hou,Jinjin Lu,Jing Liang,Yufeng Gao,Boqi Li,Shuai Gao,Yanjun Zhao,Min Gao,Jinghua Chen
Both ferroptotic therapy and immunotherapy have been widely employed in cancer treatment. However, ferroptotic cell death fails to induce dendritic cells maturation, which limits the therapeutic outcome of ferroptotic cancer therapy. To address this, the current work reports a tailored liposome to establish a positive loop between ferroptotic therapy and immunotherapy. As the key component of liposome, a unique phospholipid is designed to bear two arachidonic acid tails. The liposome is further surface-engineered with fucose ligand and physically encapsulates immunostimulatory CpG oligodeoxynucleotides (ODNs). The tailored liposome shows enhanced cellular uptake in a model 4T1 cell line. Meanwhile, the high level of reactive oxygen species in cancer cells can induce ferroptosis-specific peroxidation of DAPC and trigger the release CpG ODNs. The CpG ODNs further enable the maturation of dendritic cells and enhance the effector function of CD8 + T cells . IFN-γ released from CD8 + T cells promotes cancer cell ferroptosis via inhibiting SLC7A11 and suppressing the biosynthesis of glutathione . The tailored liposome can also act in synergism with PD-L1 antibody, resulting in enhanced anti-cancer efficacy in a 4T1 tumor-bearing mice model. This work provides a promising strategy for cancer treatment through orchestrating ferroptotic therapy and immunotherapy.
研究领域:
肿瘤学
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药学
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免疫学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Yan Zhao,Huan Wang,Yang Yang,Wendan Jia,Tong Su,Yuxin Che,Yixin Feng,Xuemei Yuan,Xuelian Wang
Background Previously, we demonstrated the therapeutic efficacy of a human papillomavirus (HPV) vaccine, including HPV16 E7 peptide and CpG oligodeoxynucleotides (CpG ODN), against small TC-1 grafted tumors. Here, we developed an HPV16 E7 peptide and CpG ODN vaccine delivered using liposomes modified with DC-targeting mannose, Lip E7/CpG, and determined its anti-tumor effects and influence on systemic immune responses and the tumor microenvironment (TME) in a mouse large TC-1 grafted tumor model.Methods L-alpha-phosphatidyl choline (SPC), cholesterol (CHOL), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol-2000)] (DSPE-PEG-2000), 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) and Mannose-PEG-DSPE, loaded with HPV16 E7 peptide and CpG ODN, were used to construct the Lip E7/CpG vaccine. The anti-tumor effects and potential mechanism of Lip E7/CpG were assessed by assays of tumor growth inhibition, immune cells, in vivo cytotoxic T lymphocyte (CTL) responses and cytokines, chemokines, CD31, Ki67 and p53 expression in the TME. In addition, toxicity of Lip E7/CpG to major organs was evaluated.Results Lip E7/CpG had a diameter of 122.21±8.37 nm and remained stable at 4°C for 7 days. Co-delivery of HPV16 E7 peptide and CpG ODN by liposomes exerted potent anti-tumor effects in large (tumor volume ≥200mm3) TC-1 grafted tumor-bearing mice with inhibition rates of 80% and 78% relative to the control and Free E7/CpG groups, respectively. Vaccination significantly increased numbers of CD4+ and CD8+ T cells, and IFN-γ-producing cells in spleens and tumors and enhanced HPV-specific CTL responses, while reducing numbers of inhibitory cells including myeloid-derived suppressor cells and macrophages. Expression of cytokines and chemokines was altered and formation of tumor blood vessels was reduced in the Lip E7/CpG group, indicating possible modulation of the immunosuppressive TME to promote anti-tumor responses. Lip E7/CpG did not cause morphological changes in major organs.Conclusion Lip E7/CpG induced anti-tumor effects by enhancing cellular immunity and improving tumor-associated immunosuppression. Mannose-modified liposomes are the promising vaccine delivery strategy for cancer immunotherapy.
研究领域:
免疫学
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肿瘤学
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药剂学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Afeng Yang,Shupei Sheng,Yun Bai,Guozheng Xing,Xuya Yu,Dunwan Zhu,Lin Mei,Xia Dong,Feng Lv
Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis therapy and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. Herein, a hydrogel/nanosystem-mediated antiangiogenesis combined immunotherapy strategy was used to regulate the tumor microenvironment by the controlled release of apatinib, CD47 antibody (aCD47), and CpG. The combination of hydrogel with nanoparticles protected drug activity and maintained a long-term slow release of the drug for maximum synergistic efficacy. Apatinib promotes vascular normalization in tumors and enhances the efficacy of aCD47-based immunotherapy. The addition of immunoadjuvant CpG further enhanced antigen presentation and stimulated the anti-tumor activity of macrophages to strengthen the efficacy of antiangiogenesis combined immunotherapy. The main effector immune cells , including CD4 + T , CD8 + T , NK, and activity DCs, were significantly increased after combination treatment, while the proportion of various immunosuppressive cells decreased significantly, especially MDSCs and M2-polarized macrophages. Based on an effective systemic immune response, the hydrogel/nanoparticle-mediated cooperative combination of antiangiogenesis and immunotherapy enhanced the synergistic effect for primary tumors and prevented metastasis for tumor treatment. The biomaterial-mediated antiangiogenesis combined immunotherapy strategy is a promising strategy for effective immunotherapy. Statement of significance Relieving immunosuppression of the tumor microenvironment is the key to restoring and rebuilding the normal anti-tumor immune defense of the body. Vascular abnormalities are directly related to the tumor immunosuppressive microenvironment, which is an important obstacle to effective immunotherapy. The combination of antiangiogenesis and immunotherapy may promote a mutually reinforcing cycle of immune reprogramming and vascular normalization to increase the effectiveness of immunotherapy. For the combination of antiangiogenesis and immunotherapy, effective drug delivery to overcome local immune tolerance and regulate the tumor microenvironment to increase therapeutic effects is an important issue. The hydrogel/nanomaterial composite system constructs a dual sustained-release system to achieve step-by-step controlled release of antiangiogenic drugs and immune immunotherapy drugs to promote cooperative combination therapy.
研究领域:
肿瘤学
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药学
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纳米技术
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免疫学
·
药物递送系统
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2017
·
IF 8.402
Fei Duan,Xiaochen Feng,Xinjian Yang,Wentong Sun,Yi Jin,Huifang Liu,Kun Ge,Zhenhua Li,Jinchao Zhang
Tumor-associated antigens (TAAs)-loaded nanoparticles are able to be actively internalized by antigen-presenting cells (APCs) and have shown promising potential in cancer immunotherapy . However, current TAAs delivery strategy exhibits limitations of complicated synthesis process, low loading efficiency and inefficient CD8 + cytotoxic T lymphocyte activation leading to unsatisfactory therapeutic effect. Thus, the construction of novel TAAs-delivery systems for enhanced cancer therapy is highly desirable. In this work, we fabricated a very simple yet powerful antigens-delivery system for cancer immunotherapy based-on pH-responsive metal-organic frameworks (MOFs) with size about 30 nm. TAAs can be loaded into MOFs in the one-pot synthesis process and released with the degradation of MOFs in the acidic environment of endo/lysosome as the result of relatively labile metal-ligand bonds. The endosomolytic nanoparticles would facilitate protein antigens escape from endo/lysosome and optimal for enhancing antigen cross-presentation. Furthermore, the introduction of immunostimulatory unmethylated cytosine-phosphate-guanine oligonucleotide (CpG) through Watson−Crick base pairing would further enhance CD8 + cytotoxic T lymphocyte responses. We demonstrated that the method to co-delivery antigens and immunostimulatory molecules was very simple, convenient and effective and showed no obvious toxicity both in vitro and in vivo . This method gave a high antigens-loading capacity and the maximal antigen encapsulating efficiency was about 55% (w/w). Additionally, the pH-responsive co-delivery system exerted enhanced antitumor outcome (about 100% survival) in B16-OVA melanoma cancers in vivo . Furthermore, we confirmed that this high rating of therapeutic effect was attributed to the recruitment of tumor-killing immunocyte. This work demonstrates the ability of pH-responsive, endosomolytic MOFs to induce strong cellular immune responses for cancer therapy by co-delivery of CpG ODN and antigens.
研究领域:
生物医学工程
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免疫学
·
癌症研究
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纳米技术
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DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 11
·2865-2876
·
IF 7.59
Mengyue Pei,Huiyang Li,Yingwei Zhu,Jian Lu,Chuangnian Zhang
Liver cancer is the most common malignant tumor and liver cancer immunotherapy has been one of the research hotspots. To induce antigen-specific antitumor immune responses against liver cancer, we developed antigen and adjuvant co-delivery nanovaccines (APPCs). Polyanionic alginate (ALG) and polycationic polyethyleneimine (PEI) were utilized to co-deliver a glypican-3 peptide antigen and an unmethylated cytosine-phosphate-guanine (CpG) adjuvant by electrostatic interactions. A cellular uptake study confirmed that APPC could promote antigen and adjuvant uptake by dendritic cells (DCs). Importantly, APPC facilitated the endosomal escape of the peptide for antigen delivery into the cytoplasm. In addition, APPC showed significant stimulation of DC maturation in vitro. APPC could also efficiently prime DCs and induce cytotoxic T lymphocyte responses in vivo. The in vitro cell viability assay and the in vivo histocompatibility showed that APPC was non-toxic within the tested concentration. This study demonstrates that the peptide antigen and the CpG adjuvant co-delivery nanovaccine have potential applications in liver cancer immunotherapy.
研究领域:
免疫学
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肿瘤学
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分子生物学
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药剂学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2022
·
IF 10.761
Junjian Shen,Minghui Lin,Mengbin Ding,Ningyue Yu,Chun Yang,Deping Kong,Haitao Sun,Zongyu Xie
Immunotherapy has recently been seen as a hopeful therapeutic device to inhibit tumor growth and metastasis, while the curative efficacy is limited by intrinsic immunosuppressive tumor microenvironment. Herein, we reported a tumor immunosuppressive microenvironment modulating hydrogel (TIMmH) platform to achieve second near-infrared (NIR-II) photothermal therapy (PTT) combined immunotherapy for durable inhibition of breast cancer. This TIMmH platform was synthesized through co-loading of NIR-II photothermal nanoagent and an immunoadjuvant cytosine-phosphateguanosine oligodeoxynucleotides (CpG ODNs) into the alginate hydrogel (ALG). Upon the administration of ALG into the tumor, the TIMmH was in situ formed via the coordination effect with Ca 2+ , locally encapsulating the semiconducting polymer nanoparticles (SP II N) and CpG in the colloid, achieving to prolong the accumulation time and prevent the premature damage and release of immunotherapeutic agents. Upon 1064-nm photoirradiation, the TIMmH SD was able to elevate the intratumoral temperature for the ablation of tumors, which could induce the apoptosis of tumor cells and achieve thermal immune activation by regulating of an immunosuppressive microenvironment. The TIMmH-mediated combined treatment effectively suppressed the growths of breast cancers, and even acquired a sustained inhibition of the lung metastasis. This study provides a novel tumor immunosuppressive microenvironment modulating hydrogel platform with NIR-II photoexcited capacity for the safe, effective and durable lung metastasis-inhibiting breast cancer treatment.
研究领域:
肿瘤学
·
材料科学
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免疫学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Cui Tang,Hui Wang,Lina Guo,Yimin Cui,Chan Zou,Jianming Hu,Hanyong Zhang,Guoping Yang,Wenhu Zhou
Atherosclerosis (AS) is a prevalent inflammatory vascular disease characterized by plaque formation, primarily composed of foam cells laden with lipids. Despite lipid-lowering therapies, effective plaque clearance remains challenging due to the overexpression of the CD47 molecule on apoptotic foam cells, inhibiting macrophage-mediated cellular efferocytosis and plaque resolution. Moreover, AS lesions are often associated with severe inflammation and oxidative stress, exacerbating disease progression. Herein, we introduce a multifunctional nanomedicine (CEZP) targeting AS pathogenesis via a “cell efferocytosis–lipid degradation–cholesterol efflux” paradigm, with additional anti-inflammatory properties. CEZP comprises poly(lactic-co-glycolic acid) nanoparticles encapsulated within a metal–organic framework shell coordinated with zinc ions (Zn2+) and epigallocatechin gallate (EGCG), enabling CpG encapsulation. Upon intravenous administration, CEZP accumulates at AS plaque sites, facilitating macrophage uptake and orchestrating AS treatment through synergistic mechanisms. CpG enhances cellular efferocytosis, Zn2+ promotes intracellular lipid degradation, and EGCG upregulates adenosine 5′-triphosphate-binding cassette transporters for cholesterol efflux while also exhibiting antioxidant and anti-inflammatory effects. In vivo validation confirms CEZP’s ability to stabilize plaques, reduce lipid burden, and modulate the macrophage phenotype. Moreover, CEZP is excreted from the body without safety concerns, offering a low-toxicity nonsurgical strategy for AS plaque eradication.
研究领域:
心血管疾病
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纳米技术
·
药理学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2020
·
IF 4.321
Tinghong Zhang,Long Zhang,Xiaoxiao Wu,Hongyan Xu,Pengyan Hao,Wenjuan Huang,Yagang Zhang,Xingjie Zan
Fully effective vaccines must induce both potent humoral and cellular immunities. Nanoparticles coencapsulating antigens and adjuvants have shown promising advantages as subunit vaccines in many aspects. However, the low loading efficiency and complicated synthesis process of these nanomaterials need to be improved. Here, we utilized hexahistidine (His6)–metal assembly (HmA) particles as carriers to codeliver ovalbumin peptides and cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs). We found that antigen/adjuvant-carrying HmA can efficiently enter into antigen-presenting cells and help the antigens escape from lysosomes to induce the maturation of these cells in vitro, characterized by increasing expression levels of costimulatory molecules and cytokines. More importantly, the vaccines with high biocompatibility can elicit strong humoral and cellular immunities by improving secretion of specific antibodies and cytokines, enhancing activation of DCs and T cells in vivo. Our results suggest that HmA provides a new approach for subunit vaccines by codelivery of antigens and adjuvants.
研究领域:
疫苗学
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免疫学
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纳米技术
·
生物医学工程
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Ling-xiao Zhang,Xia-mei Sun,Zhi Ping Xu,Rui-tian Liu
Cancer recurrence and metastasis are worldwide challenges but current bimodular strategies such as combined radiotherapy and chemotherapy (CTX), and photothermal therapy (PTT) and immunotherapy have succeeded only in some limited cases. Thus in the present study, a multifunctional nanomedicine has been rationally designed via elegantly integrating three FDA-approved therapeutics, that is, indocyanine green (for PTT), doxorubicin (for CTX), and CpG (for immunotherapy) into the structure of layered double hydroxide (LDH) nanoparticles, aiming to completely prevent the recurrence and metastasis of invasive breast cancer. This multifunctional hybrid nanomedicine has been demonstrated to eliminate the primary tumor and efficiently prevent tumor recurrence and lung metastasis through combined PTT/CTX and induction of specific and strong immune responses mediated by the hybrid nanomedicine in a 4T1 breast cancer mouse model. Furthermore, the promoted in situ immunity has significantly inhibited the growth of reinoculated distant tumors. Altogether, our multifunctional LDH-based nanomedicine has showed an excellent efficacy in invasive cancer treatment using much lower doses of three FDA-approved therapeutics, providing a preclinical/clinical alternative to cost-effectively treat invasive breast cancer.
研究领域:
肿瘤学
·
纳米医学
·
免疫疗法
·
药学科学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
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