ACS Nano
·
2025
·
IF 16
Xiaotong Chen,Lei Lei,Jiayao Yan,Xingzhou Wang,Lin Li,Qin Liu,Ying Wang,Tianran Chen,Jie Shao,Lixia Yu,Zijian Li,Lijing Zhu,Lifeng Wang,Baorui Liu
Although personalized neoantigen cancer vaccines have emerged as a promising strategy for cancer treatment, challenges remain to develop immune-stimulatory carriers which allow simultaneous transport of adjuvants and vaccines to lymph nodes (LNs). With inherent immunogenicity, genetic plasticity, and efficiency for large-scale production, M13 phages represent an attractive platform for vaccine delivery as natural bionanomaterials. Here, we report the discovery of an anti-CD40 designed ankyrin repeat protein (DARPin) and propose a bifunctional M13 ph age for neoantigen delivery based on this anti-CD40 DARPin protein (M13CD40). M13CD40-based neoantigen vaccines show improved accumulation and prolonged antigen retention in LNs compared with nontargeting phage vaccines due to the abundance of CD40-positive cells in LNs. Besides the intrinsic immunogenicity of phages, M13CD40-based neoantigen vaccines also benefit from additional CD40 stimulation due to multiple copies of anti-CD40 DARPins displayed on M13CD40 phages. Subcutaneous immunization with M13CD40-based neoantigen vaccines results in more robust antigen-specific immune responses and superior antitumor efficacy in poorly immunogenic tumor models compared with nontargeting phage vaccines. Combination therapy with PD-1 blockade further enhances T cell cytotoxicity and improves tumor control. To summarize, our findings highlight M13CD40 as a CD40 nanoagonist as well as an efficient vehicle for LN-targeted delivery of personalized neoantigen vaccines.
研究领域:
肿瘤学
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免疫学
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纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Yaohua Ke,Kai Xin,Yaping Tao,Lin Li,Aoxing Chen,Jingyi Shao,Junmeng Zhu,Dinghu Zhang,Lanqi Cen,Yanhong Chu,Lixia Yu,Baorui Liu,Qin Liu
Tumor-specific frameshift mutations encoding peptides (FSPs) are highly immunogenic neoantigens for personalized cancer immunotherapy, while their clinical efficacy is limited by immunosuppressive tumor microenvironment (TME) and self-tolerance. Here, a thermosensitive hydrogel (FSP-RZ-BPH) delivering dual adjuvants R848 (TLR7/8 agonist) + Zn 2+ (cGAS-STING agonist) is designed to promote the efficacy of FSPs on murine forestomach cancer (MFC). After peritumoral injection, FSP-RZ-BPH behaves as pH-responsive sustained drug release at sites near the tumor to effectively transform the immunosuppressive TME into an inflammatory type. FSP-RZ-BPH orchestrates innate and adaptive immunity to activate dendritic cells in tumor-draining lymph nodes and increase the number of FSPs-reactive effector memory T cells ( T EM ) in tumor by 2.9 folds. More importantly, these T EM also exhibit memory responses to nonvaccinated neoantigens on MFC. This epitope spreading effect contributes to reduce self-tolerance to maintain long-lasting anti-tumor immunity. In MFC suppressive model, FSP-RZ-BPH achieves 84.8% tumor inhibition rate and prolongs the survival of tumor-bearing mice with 57.1% complete response rate. As a preventive tumor vaccine, FSP-RZ-BPH can also significantly delay tumor growth. Overall, the work identifies frameshift MFC neoantigens for the first time and demonstrates the thermosensitive bi-adjuvant hydrogel as an effective strategy to boost bystander anti-tumor responses of frameshift neoantigens.
研究领域:
肿瘤免疫学
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生物材料学
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免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-20
·
IF 10.6
Zheng Wei,Li Shixiong,Shi Zhongliang,Su Kailing,Ding Yu,Zhang Luyue,Tang Qian,Han Jiani,Zhao Han,Wang Fengwei,Zhang Hongru,Hong Zhangyong
Background Tumor neoantigen peptide-based vaccines, systemic immunotherapies that enhance antitumor immunity by activating and expanding antigen-specific T cells, have achieved remarkable results in the treatment of a variety of solid tumors. However, how to effectively deliver neoantigens to induce robust antitumor immune responses remains a major obstacle. Results Here, we developed a safe and effective neoantigen peptide delivery system (neoantigen-ferritin nanoparticles, neoantigen-FNs) that successfully achieved effective lymph node targeting and induced robust antitumor immune responses. The genetically engineered self-assembled particles neoantigen-FNs with a size of 12 nm were obtained by fusing a neoantigen with optimized ferritin, which rapidly drainage to and continuously accumulate in lymph nodes. The neoantigen-FNs vaccine induced a greater quantity and quality of antigen-specific CD8 + T cells and resulted in significant growth control of multiple tumors, dramatic inhibition of melanoma metastasis and regression of established tumors. In addition, no obvious toxic side effects were detected in the various models, indicating the high safety of optimized ferritin as a vaccine carrier. Conclusions Homogeneous and safe neoantigen-FNs could be a very promising system for neoantigen peptide delivery because of their ability to efficiently drainage to lymph nodes and induce efficient antitumor immune responses. Graphical Abstract
研究领域:
癌症免疫疗法
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纳米技术
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2023
·Vol. 42
·期 11
·113388-113388
·
IF 8.8
Song J,Liu Y,Yin Y,Wang H,Zhang X,Li Y,Zhao X,Zhang G,Meng X,Jin Y,Lu D
Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.
研究领域:
癌症生物学
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免疫学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2024
·
IF 5.4
Yuting Hou,Zhe Wang,Zhen Chen,Lan Shuai,Yifei Pei,Binbin Sun,Yuxin Jiang,Hongsheng Wang
It is difficult to obtain specific tumor antigens, which is one of the main obstacles in the development of tumor vaccines. The vaccines containing multivalent antigens are thought to be more effective in antitumor therapy. In this study, a mRNA encoding three neoantigens of melanoma were prepared and encapsulated into the mannosylated chitosan-modified ethosomes (EthsMC) to obtain a multivalent mRNA vaccine (MmRV) for transcutaneous immunization (TCI). MmRV can effectively induce maturation of dendritic cells, with a better performance than mRNA of a single neoantigen. TCI patches (TCIPs) loading MmRV or siRNA against PDL1 (siPDL1) were prepared and applied to the skin of melanoma-bearing mice. The results showed that TCIPs significantly increase the levels of TNF-α, IFN-γ, and IL-12 in both plasma and tumor tissues, inhibit tumor growth, as well as promote infiltration of CD4+ and CD8+ T cells in the tumor tissues. Furthermore, the combination of MmRV and siPDL1 showed much better antitumor effects than either monotherapy, suggesting a synergistic effect between the vaccine and PDL1 blocker. In addition, the treatment with the TCIPs did not cause damage to the skin, blood, and vital organs of the mice, showing good biosafety. To the best of our knowledge, this work is the first to construct a noninvasive TCI system containing MmRV and siPDL1, providing a convenient and promising approach for tumor treatment.
研究领域:
肿瘤学
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免疫学
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药学
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生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2022
·
IF 18.962
Dan Zheng,Yanchu Li,Linlin Song,Tianyue Xu,Xian Jiang,Xiaomeng Yin,Yinbo He,Jinshun Xu,Xuelei Ma,Li Chai,Jie Xu,Jianping Hu,Peng Mi,Jing Jing,Hubing Shi
Radiotherapy is a compatible regimen for synergizing immune checkpoint blockade therapy by promoting immunogenic cell death. To improve the efficiency of irradiation-induced neoantigen generation, we designed and developed an ozone-carrying liposome perfluorodecalin (PFD) nano-system (O 3 [email protected] ) which promoted ozone solubility by 18.4-fold compared to that in water solution. The O 3 [email protected] particle remarkably improved the irradiation-induced hydroxyl radical generation. Evaluation of sub-cellular biodistribution indicated that the nano-system could be efficiently internalized by tumor cells. Upon released inside tumor cells, ozone generated reactive oxygen species under the stimulation of X-ray irradiation. Notably, O 3 [email protected] significantly prompted anti-tumor efficacy of radiotherapy without inducing severe adverse effects. The combo regimen with radiotherapy and ozone potently enhanced the infiltration of lymphocytes in the tumor microenvironment by inducing immunogenic cell death, releasing neoantigens, and relieving hypoxia symptom. Consequently, the combination of ozone-fueled irradiation and PD-1 blockade synergistically inhibited the growth of primary and abscopal tumors.
研究领域:
肿瘤学
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纳米技术
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放射生物学
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免疫疗法
✓ 已验证
DOI
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Jilong Wang,Chenghu Wu,Yiran Wang,Yecheng Shen,Kerui Wu,Yikai Shi,Tianshou Cao,Shanshan Yuan,Yuting Zhu,Yongheng Bai,Jinhai Huang,Yan Zhang,Junjie Deng
Low-expression antigens, especially neoantigens, pose a significant challenge in immunotherapy for low immunogenicity pancreatic cancer. Increasing the tumor mutation burden is crucial to enhance the expression of tumor antigens and improve tumor immunogenicity. However, the incomplete intervention in DNA stability hampers effective elevation of the tumor mutation burden, thus reducing the probability of neoantigen. To address this issue, we have developed a novel nano-regulator that intervenes in the DNA stability of tumor cells, thereby enhancing tumor mutations. This nano-regulator comprises metal-organic frameworks (MOFs) encapsulating DNA damage agent doxorubicin and DNA damage repair inhibitor siRNA-ATR, enabling simultaneous induction of DNA mutations and inhibition of their repair. Importantly, this regulator, named as MOF DOX&siATR , can modulate the tumor gene expression profile, induce the production of neoantigens of Atp8b1, and enhance the immunogenicity of pancreatic cancer. The characteristics of DNA stability intervention by MOF DOX&siATR hold promise for augmenting the immune response in low immunogenic tumors, making it a potential nanomedicine for the treatment of pancreatic cancer.
研究领域:
癌症生物学
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纳米技术
·
免疫疗法
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Guiyuan Chen,Xiangxia Li,Rui Li,Kecheng Wu,Zhouhang Lei,Ruike Dai,Kyle Roche,Andrew Z. Wang,Yuanzeng Min
Chemotherapeutics have the potential to increase the efficacy of cancer immunotherapies by stimulating the production of damage-associated molecular patterns (DAMPs) and eliciting mutations that result in the production of neoantigens, thereby increasing the immunogenicity of cancerous lesions. However, the dose-limiting toxicity and limited immunogenicity of chemotherapeutics are not sufficient to induce a robust antitumor response. We hypothesized that cancer cells in vitro treated with ultrahigh doses of various chemotherapeutics artificially increased the abundance, variety, and specificity of DAMPs and neoantigens, thereby improving chemoimmunotherapy. The in vitro chemotherapy-induced (IVCI) nanovaccines manufactured from cell lysates comprised multiple neoantigens and DAMPs, thereby exhibiting comprehensive antigenicity and adjuvanticity. Our IVCI nanovaccines exhibited enhanced immune responses in CT26 tumor-bearing mice, with a significant increase in CD4+/CD8+ T cells in tumors in combination with immune checkpoint inhibitors. The concept of IVCI nanovaccines provides an idea for manufacturing and artificial enhancement of immunogenicity vaccines to improve chemoimmunotherapy.
研究领域:
肿瘤学
·
免疫学
·
药学
·
生物技术
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Wen Pan,Yangyi Wang,Shaomin Tian,Xiaopeng Ma,Yuanzeng Min
Drug resistance presents a significant challenge in cancer treatment. By far, there is no effective method to solve this issue. Therapeutic cancer vaccine, which uses tumor antigens, e.g. neoantigens, to activate the hosts’ immune system to eliminate tumor cells, may be effective for overcoming tumor resistance. So, it is hypothesized that resistant tumors may have much more abundant tumor mutations in comparison to naive tumors, and the corresponding vaccine may overcome drug resistance. The proteomics data confirmes that cell lysates from resistant tumors to gemcitabine (GEM), a model drug, contain abundant tumor-associated antigens, tumor-specific antigens, damage-associated molecular patterns, and neoantigens, which can activate immune responses. Herein, to enhance antigen presentation, a mesoporous silicon nanovaccine is developed, which is loaded with antigens from GEM treated GEM-resistant triple-negative breast cancer 4T1 cells. When mice bearing GEM-resistant tumors are vaccinated, the nanovaccine displays efficacy against GEM-resistant tumors. Moreover, when combined with immunotherapy, the efficacy of the developed nanovaccine on GEM-resistant tumors are further improved by increasing intratumoral T-cell infiltrations. The work presents a new strategy for overcoming drug resistance using cancer nanovaccine, which broadens clinical application prospects.
研究领域:
肿瘤学
·
药理学
·
免疫学
·
纳米技术
·
癌症研究
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Linlin Song,Dan Zheng,Jinshun Xu,Tianyue Xu,Zhihui Liu,Huan Zhang,Yi Li,Yulan Peng,Hubing Shi
Despite revolutionary achievements have been made in clinical cancer therapy, the immune checkpoint blockade regimen still presents limited efficacy on tumors lack of neoantigens exposure. Here, we designed and synthesized an on-demand microwave-controlled ozone release nanosystem to specifically generate reactive oxygen species in tumor mass. By taking advantage of iRGD modification, the synthesized nanosystem can be specifically enriched in the tumor microenvironment and subsequently internalized by tumor cells. Triggered by the low-power microwave, ozone was released from the nanocarriers and inhibited tumor cell growth in vitro and in vivo . Molecular mechanism investigation further unraveled that the released-ozone induced cytolytic cell death through the rapid generation of reactive oxygen species such as hydroxyl radical. The tumor-specific neoantigen derived from this immunogenic cell death promoted cytotoxic T-lymphocytes infiltration, which provided a fundament for immune checkpoint blockade therapy. In the triple-negative breast cancer animal model, tumor-specific delivery of ozone significantly improved the systematical anti-tumor efficacy of the PD-1 blockade antibody. Notably, tumor-locally confined microwave-controlled release avoided systematic toxicity in the tested animals. Collectively, our nanosystem provides a novel controllable strategy for promoting immune checkpoint blockade therapy, especially in tumor types deficient in infiltrated T-lymphocytes.
研究领域:
癌症治疗
·
纳米技术
·
免疫疗法
·
肿瘤学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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