Advanced Healthcare Materials
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2024
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IF 10
Yijing Zhang,Xisen Cao,Guang Hu,Rui Ye,Li Zhang,Jie Song
Interleukin-12 (IL-12) is a critical cytokine with notable anticancer properties, including enhancing T-cell-mediated cancer cell killing, and curbing tumor angiogenesis. To date, many approaches are evaluated to achieve in situ overexpression of IL-12, minimizing leakage and the ensuing toxicity. Here, it is focused on circular single-stranded DNA (Css DNA), a type of DNA characterized by its unique structure, which could be expressed in mammals. It is discovered that Css DNA can induce sustained luciferase expression for half a year by intramuscular injection and showed effective antitumor results by intratumoral injection. Motivated by these findings, a folate-modified LNP system is now developed for the delivery of Css DNA expressing IL-12 for the therapy of 4T1 triple-negative breast cancer (TNBC). This delivery system effectively activates anti-cancer immune responses, slows tumor growth, significantly prolongs survival in animal models, and prevents tumor recurrence. After 6 months of long-term observation, the elevated level of IL-12 is still detectable in the lymph nodes and serum of the cured mice. This study highlights the long-term sustained expression capacity of Css DNA and its ability to inhibit recurrence, and the potential of tumor-targeted LNPs for Css DNA-based cancer therapy, providing a new insight into gene overexpression strategy.
研究领域:
癌症生物学
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分子生物学
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基因治疗
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纳米技术
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产品关联
DOI
PubMed
高影响因子
MEDIATORS OF INFLAMMATION
·
2016
·
IF 3.418
Xin Liu,Ning Wang,Yuanfeng Zhu,Yongjun Yang,Xiaoli Chen,Shijun Fan,Qian Chen,Hong Zhou,Jiang Zheng
Activated macrophages are the primary sources of IL-12, a key cytokine bridging innate and adaptive immunity. However, macrophages produce low amounts of IL-12 upon stimulation and the underlying regulatory mechanism remains unclear. In this study, we found a new calcium-dependent mechanism that controlled IL-12 production in LPS-treated murine macrophages. First, LPS was demonstrated to induce extracellular calcium entry in murine peritoneal macrophages and inhibition of calcium influx resulted in marked enhancement in IL-12 production. Then, withdrawal of extracellular calcium was found to suppress CaMKK and AMPK activation triggered by LPS while chemical inhibition or genetic knockdown of these two kinases augmented LPS induced IL-12 production. AMPK activation increased the NAD+/NADH ratio and activated Sirtuin 1 (SIRT1), a NAD+-dependent deacetylating enzyme and negative regulator of inflammation. Chemical inhibitor or siRNA of SIRT1 enhanced IL-12 release while its agonist suppressed IL-12 production. Finally, it was found that SIRT1 selectively affected the transcriptional activity of NF-κB which thereby inhibited IL-12 production. Overall, our study demonstrates a new role of transmembrane calcium mobilization in immunity modulation such that inhibition of calcium influx leads to impaired activation of CaMKKβ-AMPK-SIRT1 signaling pathway which lifts restriction on NF-κB activation and results in enhanced IL-12 production.
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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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2025
·Vol. 63
·期 1
·215
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IF 4.3
Wanyi Fang,Shanshan Liu,Yifei Wu,Ting Chen,Xiaohe Lu,Hui Chen
Diabetic retinopathy (DR) is a common neurovascular complication of diabetes and a leading cause of vision loss in the advanced stages. Identifying therapeutic targets to prevent early progression of DR is critical for preserving visual function. Interleukin-12 (IL-12) has emerged as a potential therapeutic agent for early-stage diabetic retinal neurodegeneration. In this study, diabetic mouse models were established, followed by intravitreal injection of IL-12 to evaluate its effects using hematoxylin and eosin staining and RNA sequencing. IL-12 treatment partially prevented the thinning of the nerve fiber layer, ganglion cell layer, and total retina. Bioinformatics analysis of RNA sequencing data revealed enrichment of microglial signatures and enhanced phagocytic function. Western blotting analysis showed that IL-12 promoted the phosphorylation of signal transducer and activator of transcription 4 (STAT4) in microglia. Bioinformatics and quantitative reverse transcription polymerase chain reaction analyses demonstrated that STAT4 activation upregulated the transcription of phagocytosis-related genes, including triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12). In vitro and in vivo experiments confirmed that IL-12 upregulates the TREM2/DAP12 signaling pathway on the microglial membrane, enhancing microglial proliferation and phagocytic activity under high-glucose conditions. These findings indicated that IL-12 mitigates early neural injury in DR by promoting microglial phagocytosis through the upregulation of TREM2/DAP12.
研究领域:
眼科学
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神经科学
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免疫学
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分子生物学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Juan Qin,Liang-Wei Si,Yi-Ming Liu,Xin-Xin Huang,Rui-Jie Du,Fei Xiong,Duo Wang,Hai-Dong Zhu
Internal radiation (IR), utilizing iodine-125 ( 125 I) seeds as a radiation source, is a clinically established modality for targeted treatment of malignant tumors. In addition to inducing DNA damage in tumor cells, IR therapy can trigger systemic antitumor immune responses, known as the abscopal effect, through immunogenic cell death (ICD). However, the gradual decline in radioactive output and the inherently limited immunogenicity of IR therapy compromise its overall efficacy, with the abscopal effect rarely observed in clinical settings. To overcome these challenges, we developed a bilayer nanofiber-coated stent integrating 125 I seed-based brachytherapy with sustained, spatiotemporally controlled delivery of interleukin-12 (IL-12). Utilizing FDA-approved PLGA and PEO polymers, the inner layer was engineered for IL-12 loading, while the outer layer acted as a regulatory barrier, achieving a biphasic release profile with sustained cytokine delivery for up to 14 days. In vivo studies demonstrated that the IL-12@IRS (IL-12-loaded 125 I internal radiation stent) effectively enhanced antigen presentation and elicited a tumor in situ vaccination effect, thereby promoting durable local and systemic antitumor immunity. This immuno-radiotherapeutic platform not only improves local tumor control but also offers a promising strategy for overcoming immune resistance and inducing robust systemic antitumor effects.
研究领域:
肿瘤学
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免疫学
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生物材料
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转化医学
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放射治疗
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Frontiers in Chemistry
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2020
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IF 3.693
Zhang Jianming,Teng Chao,Li Caolong,He Wei
Macrophages are potent to modulate inflammation via phenotypic switch and production of inflammatory factors. Baicalein (BCL) is frequently used to alleviate inflammation; however, its application is always hindered due to low solubility. Herein, BCL nanocrystals (BNRs) were prepared to improve its delivery to macrophages. The prepared BNRs have a diameter of 150 nm with a rod-like structure. The nanocrystals could be well-taken up by macrophages via the caveolar pathway and, therefore, promote the polarization switch from proinflammatory phenotype to anti-inflammatory macrophages and alleviate the inflammation via reducing production cytokine IL-12. In conclusion, the crystallization strategy is promising for the improvement of the solubility of BCL and promotion of its anti-inflammatory activities.
研究领域:
药理学
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纳米技术
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Shihui Wang,Qing Xu,Xueqian Peng,Xinman Li,Tianqing Zheng
Conventional CD3-targeting bispecific T cell engagers (BiTEs) have shown limited efficacy in solid tumors, largely due to the highly immunosuppressive tumor microenvironment (TME) and systemic T cell activation-associated toxicity. To address this challenge, we developed a peptide–MHC class I-based T cell engager platform that selectively redirects a specific subset of CD8 + T cells to tumor cells. Using the model ovalbumin (OVA) system, we engineered fusion proteins comprising an OVA peptide–H-2Kᵇ complex linked to an anti-HER2 nanobody (OVA-αHER2), enabling simultaneous engagement of OVA-specific T cells and HER2-expressing tumor cells and inducing potent tumor cell killing in vitro . To overcome the immunosuppressive TME, we further combined a HER2-targeted IL-12 fusion protein with OVA-αHER2, achieving synergistic anti-tumor responses in a mouse B16-HER2 solid tumor model. This treatment enhanced both systemic and intratumoral OVA-specific CD8 + T cell responses, accompanied by increased IFN-γ production in the TME. Together, these findings establish a modular immunotherapy strategy that integrates recruitment of a specific CD8 + T cell subset with localized cytokine-mediated immune reprogramming, providing a potential approach for HER2-positive solid tumors.
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
·
2018
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IF 3.188
Gang Chi,Xin-Xia Feng,Ying-Xia Ru,Ting Xiong,Yuan Gao,Han Wang,Zhen-Long Luo,Ran Mo,Fang Guo,Yong-Pei He,Gui-Mei Zhang,De-An Tian,Zuo-Hua Feng
Autoimmune hepatitis (AIH), a serious autoimmune liver disease, can be a lifelong illness, leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). So far the mechanisms for disease initiation are largely unknown. Here we report that the amplified non-AIH liver inflammation could promote the initiation of AIH due to the sustained increase of IL-6, IL-12, IL-4, and IL-25 in the liver. The liver injury resulting from virus (adenovirus) or chemicals (CCl 4 ) could induce an amplified (stronger/long-lasting) hepatic inflammation by releasing the ligands for TLR2/TLR4. The amplified inflammation resulted in the increase of multiple cytokines and chemokines in the liver. Among them, the sustained increase of IL-6/IL-12 resulted in the activation of STAT3 and STAT4 in hepatic CD4 + CD25 + Treg cells, thus suppressing Foxp3 gene expression to reduce the suppressive function of Treg cells in the liver, but not those in the spleen. The increase of IL-12 and the impairment of Treg function promoted Th1 response in presence of self-mimicking antigen (human CYP2D6). Intriguingly, the amplified inflammation resulted in the increase of IL-4 and IL-25 in the liver. The moderate increase of IL-4 was sufficient for cooperating with IL-25 to initiate Th2 response, but inefficient in suppressing Th1 response, favoring the initiation of autoimmune response. Consequently, either adenovirus/CYP2D6 or CCl 4 /CYP2D6 could induce the autoimmune response and AIH in the mice, leading to hepatic fibrosis. The findings in this study suggest that the amplified non-AIH inflammation in the liver could be a driving force for the initiation of autoimmune response and AIH.
研究领域:
免疫学
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肝病学
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自身免疫疾病
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2019
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IF 3.973
Menghang Zu,Heliang Song,Jiabin Zhang,Qiubing Chen,Shiqin Deng,Brandon S.B. Canup,Yi Yuan,Bo Xiao
Edible plant-derived nanoparticles (NPs) have attracted increasing attention in the treatment of ulcerative colitis (UC). Lycium barbarum (LB), a popular functional fruit, possesses various biological functions. Here, fat-soluble contents were extracted from LB and further processed into LB lipid-derived NPs (LBLNs). The resultant NPs had an average hydrodynamic diameter around 189.2 nm, narrow size distribution (polydispersity index = 0.2), and negative surface charge (-34.9 mV). Moreover, they could be efficiently taken up by UC therapy-related target cells (macrophages), and over 69.0 % of macrophages internalized LBLNs after 4 h co-incubation. We further found from the in vitro results that LBLNs had strong capacities to inhibit the secretion of the main pro-inflammatory cytokines (TNF-α and IL-12) and up-regulate the expression of the typical anti-inflammatory factor (IL-10). Finally, mice experiments confirmed that LBLNs after oral administration could specifically accumulate into inflamed colon tissues, and further attenuate UC-relevant symptoms ( e.g. , bodyweight loss, colon shortening, increase of spleen weight, and histopathological appearance, as well as ulceration). Collectively, this study demonstrates the excellent therapeutic outcomes of LBLNs against UC and provides a promising edible nanotherapeutic for UC treatment.
研究领域:
药理学
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纳米技术
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炎症性肠病
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药物递送系统
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DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-13
·
IF 3.8
Yao Fei,Yuan Qin,Yan Yichao,Liang Guoqiang,Zhou Liang,Xu Heng,Gao Shaomei,Zou Ting,Zhang Lurong
Yu-Ping-Feng-San (YPF) is a famous classical Chinese medicine formula known for its ability to boost immunity. YPF has been applied to enhance the immune status of tumor patients in clinical practice. However, there is still a lack of research on its immune regulatory effects and mechanisms in the tumor microenvironment. This study was designed to investigate the effects and mechanism of YPF on improving the immune suppression state of hepatocellular carcinoma (HCC) microenvironment. In an orthotopic mouse model of HCC, YPF improved the immune microenvironment of HCC immunosuppression, enhanced the maturation of dendritic cells (DCs), promoted the release of IL-12, and decreased the presence of JAK2, p-JAK2, STAT3, and p-STAT3 proteins in both tumor tissue and paracancerous tissues. YPF also could promote the maturation and reduce the activation of JAK2, p-JAK2, STAT3, and p-STAT3 proteins of mouse bone marrow-derived DCs induced by culture medium or tumor supernatant in vitro . Transient transfection of siRNA-STAT3 with DCs resulted in an increase in its maturation and its secretion of IL-12. On the whole, these combined effects of YPF served to ameliorate the HCC immune suppression microenvironment, which conducive to immune cells play the role of immune surveillance and killing liver cancer cells. The mechanisms of these combined effects were, at least in part, related to its inhibition of the activated JAK2-STAT3 signaling pathway in DCs within the HCC microenvironment.
研究领域:
肿瘤学
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免疫学
·
药理学
✓ 已验证
产品关联
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
·
2021
·
IF 20.722
Meng Lin,Zhenzhen Yang,Yiliang Yang,Yiwei Peng,Jiajia Li,Yitian Du,Qi Sun,Datong Gao,Quan Yuan,Yu Zhou,Xinyi Chen,Xianrong Qi
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and promote the tumor progression via multiple mechanisms. CD47 is overexpressed in most malignant tumors and acts as a “don’t eat me” signal to inhibit phagocytosis . We utilized CRISPR/Cas9 technology to knock out CD47 to guarantee the long-lasting anti-tumor immune responses. However, the reprogrammed TAMs are vulnerable to the inhibitory cytokines and tend to be transformed back into TAMs, and CD47 blockade alone may not be sufficient to elicit effective immune responses. We combined CD47 blockade with an immune-activating cytokine IL-12 for synergistic anti-tumor efficacy by genetically engineering the tumor cells into factories of IL-12 to in situ reprogram TAMs. Firstly, we designed a selective responsiveness accelerated gene delivery system named HPT-PFs that was dual modified with hyaluronic acid (HA) and tumor microenvironment sensitive peptides (TMSP) to simultaneously deliver plasmids for CD47 knockout and IL-12 production. Due to tumor-specific transfection and excellent endosome escape ability of HPT-PFs vector, more than 27% of tumor cells lost CD47 expression after HPT-PFs mediated gene editing, thus eliciting the phagocytosis by macrophages. And higher than 500 ng/ml of IL-12 was produced by tumor cells after HPT-PFs mediated pIL-12 expression, indicating the successful engineering of tumor cells into factories of IL-12. In melanoma-bearing mice models, drastic elevation of M1-polarized TAMs and secretion of inflammatory cytokines were observed when combined CD47 knockout with IL-12 production, which led to significant inhibition of tumor growth. Our study suggested that combination of CRISPR-mediated CD47 blockade with IL-12 production in tumor cells could synergistically promote macrophage-mediated immunotherapy, paving the way for CRISPR-based in situ engineering tumor cells for effective immunotherapy.
研究领域:
癌症生物学
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免疫学
·
基因治疗
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生物技术
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2017
·
IF 2.956
Zhaoxiao Yu,Chenhui Zhang,Mingliang Zhou,Qiming Li,Hui Li,Wei Duan,Xue Li,Yonghong Feng,Jianping Xie
Tuberculosis (TB), caused by Mycobacterium tuberculosis , remains a formidable threat to global public health . The successful intracellular persistence of M . tuberculosis significantly contributes to the intractability of tuberculosis. Proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) are mycobacterial exclusive protein families that widely reported to be involved in the bacterial virulence , physiology and interaction with host. Rv2770c (PPE44), a predicted virulence factor , was up-regulated upon the infected guinea pig lungs. To investigate the role of Rv2770c, we heterologously expressed the PPE44 in the nonpathogenic fast-growing M . smegmatis strain. Subcellular location analysis demonstrated that Rv2770c is a cell wall associated protein, suggestive of a potential candidate involved in host-pathogen interaction. The Rv2770c can enhance M . smegmatis survival within macrophages and under stresses such as H 2 O 2 , SDS, diamide exposure, and low pH condition. M . smegmatis expressing Rv2770c is more virulent as testified by the increased death of macrophages and the increased expression of interlukin-6 (IL-6) and interlukin-12p40 (IL-12p40). Moreover, Rv2770c altered the secretion of IL-6 and IL-12p40 of macrophages via NF-κB, ERK1/2 and p38 MAPK axis. Taken together, this study implicated that Rv2770c was a virulent factor actively engaged in the interaction with host macrophage.
研究领域:
微生物学
·
免疫学
·
分子生物学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）