MOLECULAR CELL
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2021
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IF 17.97
Zihao Dai,Haining Liu,Junbin Liao,Cheng Huang,Xiaoxue Ren,Wanjie Zhu,Shenghua Zhu,Baogang Peng,Shaoqiang Li,Jiaming Lai,Lijian Liang,Lixia Xu,Sui Peng,Shuibin Lin,Ming Kuang
Summary Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N 7 -methylguanosine (m 7 G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo . Mechanistically, m 7 G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m 7 G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m 7 G tRNA modification in promoting ICC tumorigenesis and progression in vivo . Our study uncovers the important physiological function and mechanism of METTL1-mediated m 7 G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.
研究领域:
癌症生物学
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分子生物学
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转化医学
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DOI
PubMed
高影响因子
ADVANCED MATERIALS
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2021
·Vol. 33
·期 34
·2101707
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IF 30.849
Min Li,Sanpeng Li,Yixuan Huang,Haixia Chen,Songya Zhang,Zhicheng Zhang,Weigang Wu,Xiaobin Zeng,Boping Zhou,Bin Li
The transfer of foreign synthetic messenger RNA (mRNA) into cells is essential for mRNA-based protein-replacement therapies. Prophylactic mRNA COVID-19 vaccines commonly utilize nanotechnology to deliver mRNA encoding SARS-CoV-2 vaccine antigens, thereby triggering the body's immune response and preventing infections. In this study, a new combinatorial library of symmetric lipid-like compounds is constructed, and among which a lead compound is selected to prepare lipid-like nanoassemblies (LLNs) for intracellular delivery of mRNA. After multiround optimization, the mRNA formulated into core–shell-structured LLNs exhibits more than three orders of magnitude higher resistance to serum than the unprotected mRNA, and leads to sustained and high-level protein expression in mammalian cells. A single intravenous injection of LLNs into mice achieves over 95% mRNA translation in the spleen, without causing significant hematological and histological changes. Delivery of in-vitro-transcribed mRNA that encodes high-affinity truncated ACE2 variants (tACE2v mRNA) through LLNs induces elevated expression and secretion of tACE2v decoys, which is able to effectively block the binding of the receptor-binding domain of the SARS-CoV-2 to the human ACE2 receptor. The robust neutralization activity in vitro suggests that intracellular delivery of mRNA encoding ACE2 receptor mimics via LLNs may represent a potential intervention strategy for COVID-19.
研究领域:
纳米技术
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分子生物学
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药学
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病毒学
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治疗学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
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IF 26.8
Shifeng Ling,Yixiang Zhang,Yanyang Chen,Wei He,Tianqi Wu,Juan Wang,Yingying Wei,Min Lu,Wei-Li Zhao,Qingfeng Li,Yawei Du,Wenguo Cui
Mitochondrial dysfunction-mediated ribosomal translation suppression is a hallmark of aging and a major driver of degenerative diseases, limiting mRNA therapy efficacy. Here, ionizable coenzyme Q10 (iCoQ10)-engineered lipid/fiber microplexes (iCLNP@SF) are developed that restore the mitochondrial-ribosomal axis to enhance mRNA translation. iCoQ10 replaces conventional ionizable lipids to form prodrugged lipid nanoparticles (iCLNP), stabilized by injectable polydopamine‑modified short fibers for in situ administration. In vitro efficacy assessments showed that iCLNP@SF synergistically enhanced mitochondrial metabolism and mRNA translation in senescent cells. Further mechanistic studies revealed that iCLNP stabilized mitochondrial membrane potential, suppressed cGAS-STING activation, and reduced eIF2α phosphorylation, thereby enhancing translation. In vivo, iCLNP@SF delivery of Gas6 mRNA increased hair follicle density by ≈50% in an androgenetic alopecia mouse model, while Runx2 mRNA delivery raised new bone formation (BV/TV) to ≈40% in defect models, both markedly outperforming conventional LNPs. Together, these findings highlight a strategy that improves mRNA therapy for degenerative diseases.
研究领域:
分子生物学
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药剂学
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老年医学
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基因治疗
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线粒体生物学
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转化医学
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产品关联
DOI
PubMed
高影响因子
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