PHARMACOGENOMICS
·
2020
·
IF 2.339
Keguang Chen,Ruichen Guo,Chunmin Wei
Aim: To evaluate whether the synonymous mutant rs2515641 could affect cytochrome P450 2E1 (CYP2E1) expression and the response to acetaminophen (APAP) or triptolide (TP) treatment. Materials & methods: HepG2 cells were transfected with lentiviral vector containing either CYP2E1-1263C or CYP2E1-1263T. Some of these recombinant cells were then treated with APAP or TP. CYP2E1 gene expression was detected by PCR and western blot. Results:CYP2E1 gene expression decreased significantly both in mRNA and protein level after rs2515641 mutation, indicating that this polymorphism can affect both transcription and translation. Furthermore, rs2515641 mutation dramatically changes the response of CYP2E1 expression to APAP or TP treatment. Conclusion: Rs2515641 significantly changes CYP2E1 expression and function, which would be expected to affect drug disposition and response.
研究领域:
药理学
·
分子生物学
·
遗传学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Feifan Yin,Murilege Chao,Jinhua Chen,Yanheng Yao,Miao He,Qiufeng Wang,Wenting Cheng,Yongliang Cai,Zhongyun Wang,Yang Xiang
mRNA vaccines have been developed as a captivating and highly prospective avenue for the advancement of immunotherapy. With the advancement of antitumor mRNA vaccines into clinical trials, it is important to monitor the levels of nucleic acid drugs. In this study, we have engineered a new biosensor for melanoma-associated antigen mRNA vaccines utilizing an adjustable structure MNAzyme (ASM) activated by an entropy-driven circuit (EDC). The EDC process is specifically triggered by the target mRNA through the exposed toehold, achieving initial amplification. As a result of proximity effects facilitated by the EDC products, ASM is successfully assembled and activated by undergoing conformational transformation because of rational sequence design, continuously cleaving the fluorescence reporter and realizing the second round of signal amplification. Compared with conventional DNAzyme, ASM can effectively reduce signal leakage and concurrently preserve cleavage efficiency, benefiting from the stable presence of a stem-loop hairpin and an adjustable molecular switch. Moreover, composed only of DNA with highly integrated sequences, this method could realize detection in an enzyme-free, one-step, and one-pot detection manner. Finally, EDC-ASM demonstrates high programmability, excellent specificity, and sensitivity in nucleic acid detection, providing a novel strategy for the study of antitumor mRNA vaccines.
研究领域:
分子生物学
·
生物传感
·
肿瘤免疫治疗
·
核酸分析
·
转化医学
·
药物监测
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Chao Liu,Yuhao Jiang,Wenliang Xue,Jinyu Liu,Zihao Wang,Jianhong Luo,Xinsong Li
Lipid nanoparticles (LNP) have shown great promise in clinical applications for delivering mRNA. Targeted delivery of mRNA to particular tissues or organs is essential for precise therapeutic outcomes and minimized side effects in various disease models. However, achieving targeted delivery beyond the liver is a challenge based on current LNP formulations. In this report, we synthesized four ionizable cholesterol analogs by attaching two tertiary amine groups onto the head of a cholesterol-like structure and incorporated them as a fifth component into conventional commercial LNPs based on ALC-0315 or SM-102. Selective targeting delivery of mRNA is achieved by adjusting the proportion of the fifth component in the LNP. Specifically, a spleen-targeted 0315-Ergo-40% formulation demonstrated an impressive 95% delivery efficiency, while a lung-targeted 102-Sito-40% formulation achieved up to 78%. Moreover, when this strategy is applied to a self-developed ionizable lipid named U-101 instead of ALC-0315 or SM-102, the targeting delivery efficiencies to the spleen and lungs reach 96 and 71%, respectively. Multiple assessments suggest that inclusion of the fifth component does not compromise LNP stability, as indicated by consistent particle size, polydispersity index (PDI), and encapsulation efficiency. Furthermore, the test results of liver and kidney function and immunogenicity reveal no increase of toxicity in vivo following the introduction of the fifth component. Additional studies on in vitro cytotoxicity, lysosomal escape, and cellular transfection efficiency confirm that the fifth component does not diminish delivery performance. Taken together, the incorporation of ionizable cholesterol analogs leads to targeting of LNP delivery, which features strong organ selectivity, high safety, and suitability for further evaluation.
研究领域:
纳米技术
·
药学科学
·
分子生物学
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
Cell Discovery
·
2023
·Vol. 9
·期 1
·1-15
·
IF 33.5
Ai Liangxia,Li Yafei,Zhou Li,Yao Wenrong,Zhang Hao,Hu Zhaoyu,Han Jinyu,Wang Weijie,Wu Junmiao,Xu Pan,Wang Ruiyue,Li Zhangyi,Li Zhouwang,Wei Chengliang,Liang Jianqun,Chen Haobo,Yang Zhimiao,Guo Ming,Huang Zhixiang,Wang Xin,Zhang Zhen,Xiang Wenjie,Sun Dazheng,Xu Lianqiang,Huang Meiyan,Lv Bin,Peng Peiqi,Zhang Shangfeng,Ji Xuhao,Luo Huiyi,Chen Nanping,Chen Jianping,Lan Ke,Hu Yong
Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, most current mRNA delivery platforms need to be stored at −20 °C or −70 °C due to their poor stability, which severely restricts their availability. Herein, we develop a lyophilization technique to prepare SARS-CoV-2 mRNA-lipid nanoparticle vaccines with long-term thermostability. The physiochemical properties and bioactivities of lyophilized vaccines showed no change at 25 °C over 6 months, and the lyophilized SARS-CoV-2 mRNA vaccines could elicit potent humoral and cellular immunity whether in mice, rabbits, or rhesus macaques. Furthermore, in the human trial, administration of lyophilized Omicron mRNA vaccine as a booster shot also engendered strong immunity without severe adverse events, where the titers of neutralizing antibodies against Omicron BA.1/BA.2/BA.4 were increased by at least 253-fold after a booster shot following two doses of the commercial inactivated vaccine, CoronaVac. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity and significantly improves their accessibility, particularly in remote regions.
研究领域:
病毒学
·
免疫学
·
药学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Bin Wang,Maoping Tang,Qijing Chen,William Ho,Yilong Teng,Xiaojian Xiong,Zhitong Jia,Xiuling Li,Xiaoyang Xu,Xue-Qing Zhang
T cell exhaustion has emerged as a major hurdle that impedes the clinical translation of stimulator of interferon genes (STING) agonists. It is crucial to explore innovative strategies to rejuvenate exhausted T cells and potentiate the antitumor efficacy. Here, we propose an approach utilizing MSA-2 as a STING agonist, along with nanoparticle-mediated delivery of mRNA encoding interleukin-12 (IL-12) to restore the function of T cells. We developed a lipid nanoparticle (DMT7-IL12 LNP) that encapsulated IL12 mRNA. Our findings convincingly demonstrated that the combination of MSA-2 and DMT7-IL12 LNP can effectively reverse the exhausted T cell phenotype, as evidenced by the enhanced secretion of cytokines, such as tumor necrosis factor alpha, interferon gamma, and Granzyme B, coupled with reduced levels of inhibitory molecules such as T cell immunoglobulin and mucin domain-3 and programmed cell death protein-1 on CD8+ T cells. Furthermore, this approach led to improved survival and tumor regression without causing any systemic toxicity in melanoma and lung metastasis models. These findings suggest that mRNA encoding IL-12 in conjunction with STING agonists has the potential to confer superior clinical outcomes, representing a promising advancement in cancer immunotherapy.
研究领域:
癌症研究
·
免疫学
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Zijin Luo,Yi Lin,Yanan Meng,Mengyao Li,Hongyu Ren,Haoping Shi,Qiang Cheng,Tuo Wei
The successful application of mRNA vaccines in preventing and treating infectious diseases highlights their potential as therapeutic vaccines for cancer treatment. However, unlike infectious diseases, effective antitumor therapy, particularly for solid tumors, necessitates the activation of more powerful cellular and humoral immunity to achieve clinical efficacy. Here, we report a spleen-targeted mRNA vaccine (Mn@mRNA-LNP) designed to deliver tumor antigen-encoding mRNA and manganese adjuvant (Mn2+) simultaneously to dendritic cells (DCs) in the spleen. This delivery system promotes DC maturation and surface antigen presentation and stimulates the production of cytotoxic T cells. Additionally, Mn2+ codelivered in the system serves as a safe and effective immune adjuvant, activating the stimulator of interferon genes (STING) signaling pathway and promoting the secretion of type I interferon, further enhancing the antigen-specific T cell responses. Mn@mRNA-LNP effectively inhibits tumor progression in established melanoma and colon tumor models as well as in a model of tumor recurrence after resection. Notably, the combination of Mn@mRNA-LNP with immune checkpoint inhibitors further enhances complete tumor suppression and prolonged the overall survival in mice. Overall, this “All-in-One” mRNA vaccine significantly boosts antitumor immunity responses by improving spleen targeting and immune activation, providing an attractive strategy for the future clinical translation of therapeutic mRNA vaccines.
研究领域:
癌症免疫治疗
·
疫苗开发
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 18
·9199
·
IF 4.9
Jia Fu,Yanan Zhang,Yifan Lv,Ruilin Li,Hongchen Gu,Jingxing Yang
Genetic engineering of macrophages, particularly for chimeric antigen receptor macrophage (CAR-M) therapy, holds great promise for immunotherapy, yet is constrained by the challenge of efficient gene delivery into primary macrophages, which are notoriously resistant to transfection. While conventional strategies focus on optimizing the physicochemical properties of lipid nanoparticles (LNP), they often fail to overcome the intrinsic biological barriers of these cells. Here, we introduced a “bioactive nanocarrier” paradigm, hypothesizing that incorporating a cellular modulator directly into LNP structure can synergistically overcome these barriers. We designed and synthesized a novel LNP by integrating the pro-inflammatory fatty acid, arachidonic acid (ARA), as a functional structural component (ARA-LNP). Systematic optimization of the ARA content and mRNA payload revealed a formulation that achieves high transfection efficiency (83.76%) in primary M2-polarized bone marrow-derived macrophages (BMDMs), a cell type that recapitulates pro-tumoral phenotype in the tumor microenvironment. Leveraging this advanced delivery platform, we successfully generated HER2-targeting CAR-M that demonstrated potent and specific phagocytic activity against HER2-expressing tumor cells in vitro. This work presents a powerful strategy where the nanocarrier itself transiently modulates the target cell state to enhance gene delivery, providing a new design principle for engineering macrophages and other hard-to-transfect immune cells for therapeutic applications.
研究领域:
免疫学
·
肿瘤学
·
纳米医学
·
基因治疗
·
转化医学
·
分子药剂学
·
细胞工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Chao Liu,Yuhao Jiang,Wenliang Xue,Jinyu Liu,Zihao Wang,Xinsong Li
Ionizable lipid-based lipid nanoparticles (LNP) play a crucial role in the delivery of mRNA. The hydrophobic tail of ionizable lipid affects the formation of LNP and the release of mRNA. In this report, we focus on the effect of the number, chain length, and double bond number of the hydrophobic tail on the delivery efficiency. First, a series of ionizable lipids with two, three and four tails were synthesized and characterized featured with imidazole group as the head. The ionizable lipids derived LNP were prepared using a microfluidic co-mixing device, yielding particles primarily in the size range of 100 to 150 nm, with a polydispersity index (PDI) below 0.2. Screening identified ionizable lipids with four tails exhibiting superior delivery efficiency, of which U-15, U-17, U-18 and U-19 demonstrated the highest performance. Additionally, the U-19 significantly prolongs mRNA expression duration, and along with specific extrahepatic delivery effect compared to ALC-0315. Tissue slice tests on representatives (U-06: two tails, U-19: four tails, U-29: three tails) revealed no notable abnormalities. Analysis of immunogenicity, liver and kidney function tests indicated that all samples exhibited no evident immunogenicity or in vivo toxicity. Findings from tests on lysosome escape, cell transfection, and cytotoxicity revealed excellent in vitro delivery effectiveness. In summary, among the 35 imidazole-based ionizable lipids screened, optimal effects were exhibited by four tails, which providing a new strategy for the development of ionizable lipids.
研究领域:
药学
·
纳米技术
·
分子生物学
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Wenwen Sun,Shiyun Huang,Zhihong Sun,Qi Zhao,Jie Li,Baoyu Wen,Jie Liu,Guanjun Deng,Chengming Sun
Immune checkpoint blockade (ICB) has shown promising potential for treating triple-negative breast cancer (TNBC), but its efficacy is limited, mainly due to the “cold,” suppressive immune tumor microenvironment (TME). Therefore, improving the TME is crucial for enhancing therapeutic effects against TNBC. Here, we presented a multifunctional nanotherapeutic platform (ALEvs@LNPs) designed to combine cytokine-sensitized mild photothermal therapy, ICB, and interleukin-2 (IL2) mRNA therapy to reprogram the TME, thereby improving the efficacy of ICB therapy in TNBC. Tumor cell-derived exosome-camouflaged lipid nanoparticles with antilymphocyte activation gene-3 (LAG3) were developed to codeliver the photothermal agent IR806, IL2 mRNA, and LAG3 inhibitory antibody (anti-LAG3). Mild photothermal therapy facilitated the reprogramming of “cold” tumors into “hot,” thereby enhancing the therapeutic effects of ICB. Meanwhile, ICB also promoted cytokine secretion, increasing the sensitivity of tumor cells to heat. Additionally, IL2 mRNA therapy induced T-cell proliferation and activation, further augmenting the efficacy of ICB. Together, these three therapies established a positive feedback loop that enhanced the therapeutic effects of ICB. This multifunctional nanotherapeutic platform effectively reprogrammed the “cold,” suppressive immune TME, offering a promising strategy for TNBC treatment.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2025
·
IF 3
Chao Liu,Yuhao Jiang,Wenliang Xue,Jinyu Liu,Zihao Wang,Xinsong Li
Lipid nanoparticles (LNP) are recognized as the most efficient non-viral carriers for the delivery of nucleic acids including small interfering RNA (siRNA) and messenger RNA (mRNA). Ionizable lipid within the system is pivotal component influencing encapsulation, endosomal escape, delivery efficiency and immunogenicity. Accordingly, the precision design of ionizable lipids is a key step in the development of LNP. In this report, we constructed sixteen Janus dendritic ionizable lipids by varying numbers and alkyl chain length of tails based on different ionizable head containing hydroxyl and tertiary amine groups. The corresponding LNP were prepared by using microfluidic mixing device, with all samples exhibiting particle size around 100 nm and polydispersity index (PDI) below 0.2. In vivo validation demonstrates that two optimized ionizable lipids containing two hydroxy groups, two tertiary amines and six hydrophobic chain tails (U-502, U-503) show superior delivery efficiency compared to lipids with less tails and commercial ALC-0315. Hematoxylin and Eosin (H&E) staining of tissues, immunogenicity, liver and kidney function tests additionally confirm that both ionizable lipids have favorable biocompatibility and low in vivo toxicity. Lysosomal escape and cell transfection data verify the in vitro delivery efficacy of these LNP. Taken together, Janus dendritic lipids with fine designed ionizable head and multiple hydrophobic tails have improved mRNA delivery efficiency and biosafety, which may be promise in the development of delivery system.
研究领域:
药剂学
·
分子生物学
·
纳米技术
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
COMPUTERS IN BIOLOGY AND MEDICINE
·
2024
·
IF 7
Jianan Li,Yan Sun,Haoran Bi
Diazinon (DZN), a persistent organophosphate insecticide, has been associated with neurotoxic effects, particularly in the hippocampus. However, the specific molecular mechanisms of DZN-induced hippocampal toxicity remain unknown. In this study, we analyzed the mRNA and miRNA expression patterns of HT22 cells following exposure to DZN (125 μM), and the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted subsequently. The integration of miRNA sequencing (miRNA-seq) and mRNA sequencing (mRNA-seq) data identified 33 differentially expressed miRNAs (DEMIs, 15 up-regulated and 18 down-regulated) and 271 differentially expressed mRNAs (DEMs, 69 up-regulated and 202 down-regulated) targeted by the DEMIs. Moreover, the 3 most central mRNAs (ITGAV, FN1, and EGFR) and 7 associated miRNAs (mmu-miR-700-5p, mmu-miR-26a-2-3p, mmu-miR-452-3p, mmu-miR-25-3p, mmu-miR-582-5p, mmu-miR-467a-5p, and mmu-miR-467b-5p) were screened and validated using quantitative real-time PCR. Furthermore, the GO analysis revealed that the identified DEMs were enriched in biological adhesion extracellular matrix, and growth factor binding, while the KEGG analysis suggested that the enriched DEMs were involved in ECM-receptor interaction, mTOR signaling pathway, MAPK signaling pathway, and AMPK signaling pathway. Our results may aid in elucidating the underlying mechanisms associated with DZN-induced hippocampal toxicity and provide valuable insights into the pathogenesis of neurotoxicity triggered by other organophosphorus pesticides.
研究领域:
神经毒理学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2023
·
IF 4.8
Sijia Han,Xueying Jin,Tianyu Hu,Feng Chi
Non-SMC condensin II complex subunit G2 (NCAPG2) is one of the three non-SMC subunits in condensin II, which plays a vital role in regulating chromosome condensation and segregation. Although the tumor-promoting role of NCAPG2 has been reported in several solid malignancies, its function in breast invasive carcinoma (BRCA) remains unknown. Data both from GEPIA and GSE36295 indicated that NCAPG2 mRNA expression was abnormally upregulated in cancer tissues, which was further verified in 40 paired BRCA and para-carcinoma samples. Kaplan-Meier Plotter further illustrated that BRCA patients with higher NCAPG2 expression have a poorer prognosis. Functional experiments carried out in two BRCA cell lines (MCF-7 and T-47D) showed that NCAPG2-silenced BRCA cells acquired less aggressive behavior — weakened growth and metastasis both in vitro and in vivo. Label-free proteomics quantified the protein expression patterns in MCF-7 cells, and the results revealed 684 differentially expressed proteins (|log 2 FC| > 1 and P < 0.05) downstream to NCAPG2. Interestingly, poly(C)-binding protein 2 (PCBP2), an RNA binding protein previously known to increase RNA stability of its target genes, was found to directly bind to and protect NCAPG2 mRNA from degradation—PCBP2 knockdown accelerated the degradation half-life time of NCAPG2 mRNA from approximately 8 h to 5 h. Taken together, our study indicates that NCAPG2 acts as a novel contributor to BRCA growth and metastasis under the regulation of PCBP2, providing insights into BRCA treatment.
研究领域:
癌症生物学
·
分子生物学
·
基因组学
·
蛋白质组学
·
细胞生物学
✓ 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）