ACS Nano
·
2025
·
IF 16
Kexin Cui,Zhang Fangming,Tianzi Shi,Siyu Zhao,Yixuan Zhou,Xiong Liu,Yong Hu,Zhaoyu Hu,Li Kong,Zhiping Zhang
Ionizable lipids are crucial for the effective delivery of mRNA by using lipid nanoparticles (LNPs). Endowing ionizable lipids with tailored biological properties could potentially augment the therapeutic efficacy of mRNA-based treatments. Herein, a functional vitamin E (VE)-based lipid library with distinct head groups was designed and synthesized. Due to the presence of VE, these lipids inherently exhibited immunomodulatory properties, including the promotion of cellular uptake, dendritic cells maturation, and antigen presentation. Through iterative optimization of the LNP components and the architecture of ionizable lipids, the correlation between the structure of ionizable lipids and their mRNA delivery efficiency has been established, leading to the finding of the most effective delivery formulation. Benefiting from the high mRNA delivery efficiency and the immunomodulatory function of LNPs themselves, VE-based LNPs have demonstrated complete remission in colon cancer by delivering mIL-12, which offered a beneficial combination with immune checkpoint blockade. The proposed functional LNPs were anticipated to furnish potential delivery systems for mRNA-based cancer treatments.
研究领域:
生物技术
·
肿瘤学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small Methods
·
2020
·Vol. 5
·期 4
·2001047
·
IF 12.13
Jianqiao Chang,Yu Zhang,Yike Li,Ziwei Han,Fei Tian,Chao Liu,Qiang Feng,Yuguang Wang,Jiashu Sun,Lu Zhang
Detection of mRNA expression in live cells during treatment is a challenging task, despite its importance in tumor biology and potential therapeutic leads. Here a multilayer ratiometric fluorescent nanomachine for live-cell perturbation and imaging of mRNA at single cell resolution is reported. The nanomachines fabricated by microfluidic approaches consist of fluorescent polymeric cores and multiple lipid layers, which can efficiently deliver siRNA and molecular beacons (MBs) to cytosol and then release the cargo in a sequential way. The siRNA molecules released from the outer lipid layers lead to silencing of multidrug resistance 1 (MDR1) gene, and the MBs from the middle lipid layers detect the presence of MDR1 mRNA. The fluorescent ratio of MBs to fluorescent polymeric cores positively correlates with the expression level of MDR1 mRNA in MCF-7/ADR cells during siRNA treatment. The nanomachines provide comparable results with traditional qPCR for quantifying mRNA, showing great potential for modulation and imaging of intratumoral mRNA in vitro and in vivo.
研究领域:
生物技术
·
分子生物学
·
癌症研究
·
纳米技术
✓ 已验证
DOI
PubMed
高影响因子
Natural Product Communications
·
2019
·
IF 0.554
Keling Cheng,Xuan Zeng,Hao Wu,Weiwei Su,Weiyang Fan,Yang Bai,Hongliang Yao,Peibo Li
Naringin (NRG) is a common dietary flavonoid in citrus fruits and has been documented to possess multiple pharmacological activities, including anti-oxidant, anti-inflammatory, and neuroprotective effects. Naringin is frequently consumed in combination with common clinical drugs. To date, the effects of NRG on cytochrome P450 enzymes have not been fully investigated yet. In this study, the activities of hepatic CYP1A2, CYP2D2, CYP2C9, CYP2C19, and CYP2E1 in rats after the continuous oral administration of NRG (50 and 500 mg/kg) were evaluated using cocktail probe-drug method. The concentrations of 5 probe drugs (phenacetin, dextromethorphan, diclofenac sodium, omeprazole, and chlorzoxazone) in rat plasma were simultaneously determined with a validated HPLC-MS/MS (high performance liquid chromatography-tandem mass spectrometry) method and then used to calculate corresponding pharmacokinetic parameters. Compared with the control group, the AUC(0-t), AUC(0-∞), t 1/2, and C max of each probe drug in treatment groups showed no significant differences. Meanwhile, fluorescence quantitative polymerase chain reaction (FQ-PCR) analysis revealed that NRG did not significantly affect the mRNA expressions of genes CYP1a2, CYP2d2, CYP2c6, CYP2c11, and CYP2e1 in rat liver. Based on these results, it could be concluded that NRG showed no significant effects on the activities and mRNA expressions of tested CYP450 in rats.
研究领域:
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2022
·
IF 14.903
Zhejie Chen,Wei Hao,Caifang Gao,Yangyang Zhou,Chen Zhang,Jinming Zhang,Ruibing Wang,Yitao Wang,Shengpeng Wang
With the development of synthesis technology, modified messenger RNA (mRNA) has emerged as a novel category of therapeutic agents for a broad of diseases. However, effective intracellular delivery of mRNA remains challenging, especially for its sensitivity to enzymatic degradation. Here, we propose a polyphenol-assisted handy delivery strategy for efficient in vivo delivery of IL-10 mRNA. IL-10 mRNA binds to polyphenol ellagic acid through supramolecular binding to yield a negatively charged core, followed by complexing with linear polyetherimide and coating with bilirubin-modified hyaluronic acid to obtain a layer-by-layer nanostructure. The nanostructure specifically up-regulated the level of IL-10, effectively inhibited the expression of inflammatory factors, promoted mucosal repair, protected colonic epithelial cells against apoptosis, and exerted potent therapeutic efficacy in dextran sulfate sodium salt-induced acute and chronic murine models of colitis. The designed delivery system without systemic toxicity has the potential to facilitate the development of a promising platform for mRNA delivery in ulcerative colitis treatment.
研究领域:
药学
·
分子生物学
·
纳米技术
·
炎症性肠病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2024
·
IF 4.5
Xinxi Cai,Aftab Ullah,Rui Qian,Junming Cui,Lin Wu,Song Shen
Messenger RNA (mRNA) based therapy is becoming a research hot spot in the fight against a wide variety of disease especially COVID-19, however, developing a safe and efficient delivery system to protect mRNA from degradation is a significant challenge. Here, we have designed a novel system based on poly- l -lysine modified bovine serum albumin nanoparticles for the delivery of mRNA. Cationic protein nanoparticles were prepared (BSA-PLL@MCM), followed by coating with macrophage cell membranes to enhance the protective effect and transfection efficiency. The bio nano vector has an excellent safety profile both in vitro and vivo settings and the encapsulated mRNA was successfully delivered in in vitro and in vivo settings. These findings demonstrate that the protein-based nanoparticle can be regarded as an alternative delivery vector for mRNA, thus providing a novel idea for vector development.
研究领域:
药学
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 3
·1-16
·
IF 8.1
Ma Lan,Zhou Xi,Yao Siyue,Zhang Xinyu,Mao Ji,Vona Barbara,Fan Liwen,Lou Shu,Li Dandan,Wang Lin,Pan Yongchu
Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of m 6 A modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3 -knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA m 6 A methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of m 6 A-modified PSEN1 , while decreased METTL3-mediated m 6 A methylation hindered β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of the Wnt/β-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.
研究领域:
发育生物学
·
分子生物学
·
遗传学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Gege Zeng,Zepeng He,Haihong Yang,Zhan Gao,Xueer Ge,Lixin Liu,Zhijia Liu,Yongming Chen
Much of current clinical interest has focused on mRNA therapeutics for the treatment of lung-associated diseases, such as infections, genetic disorders, and cancers. However, the safe and efficient delivery of mRNA therapeutics to the lungs, especially to different pulmonary cell types, is still a formidable challenge. In this paper, we proposed a cationic lipid pair (CLP) strategy, which utilized the liver-targeted ionizable lipid and its derived quaternary ammonium lipid as the CLP to improve liver-to-lung tropism of four-component lipid nanoparticles (LNPs) for in vivo mRNA delivery. Interestingly, the structure–activity investigation identified that using liver-targeted ionizable lipids with higher mRNA delivery performance and their derived lipid counterparts is the optimal CLP design for improving lung-targeted mRNA delivery. The CLP strategy was also verified to be universal and suitable for clinically available ionizable lipids such as SM-102 and ALC-0315 to develop lung-targeted LNP delivery systems. Moreover, we demonstrated that CLP-based LNPs were safe and exhibited potent mRNA transfection in pulmonary endothelial and epithelial cells. As a result, we provided a powerful CLP strategy for shifting the mRNA delivery preference of LNPs from the liver to the lungs, exhibiting great potential for broadening the application scenario of mRNA-based therapy.
研究领域:
药学
·
纳米技术
·
分子生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 19
·4713
·
IF 4.2
Wei He,Qi Geng,Guiying Ji,Ji Li,Dan Wang,Yucai He,Qiuheng Jin,Jianren Ye
The remarkable efficacy of COVID-19 vaccines has established mRNA as a highly promising biomedical technology. However, the adequate application of mRNA therapeutics necessitates additional measures to mitigate the inherent immunogenicity, which is predominantly caused by dsRNA. As a byproduct of the in vitro transcription of mRNA, dsRNA was reported to be originated through several distinct mechanisms, including the extension of 3′ loop-back hairpins, the extension of hybridized abortive transcripts, and promoter-independent transcription. The intricate mechanisms involved pose a dilemma as the reduction in dsRNA results in a concomitant decrease in other critical quality attributes of mRNA. Here, we demonstrate that the promoter binding motifs of T7 RNA polymerase directly impact the production of promoter-independent transcription-based dsRNA. Specifically, the G753A mutation significantly reduces the formation of dsRNA byproducts, which can further combine with modified nucleotides to enhance the effectiveness of dsRNA mitigation and with previously reported high-integrity mutation K389A to minimize side effects. Accordingly, the present study reports a cost-effective approach to synthesize high-purity, less immunostimulatory mRNA by using an engineered T7 RNA polymerase mutant.
研究领域:
分子生物学
·
生物技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Ping Chen,Xi He,Yue Hu,Xiao-Li Tian,Xiao-Qi Yu,Ji Zhang
In recent years, the application of mRNA vaccine-based tumor immunotherapy invigorated anti-tumor therapy. However, the low efficiency of mRNA delivery and the lack of targeting ability in vivo are the major obstacles to achieving highly efficient immunotherapy. In this work, we report a chemical library of amphiphilic carbon dots (ACDs) and the synthesized ACDs were applied to mRNA delivery, bio-imaging, and tumor immunotherapy. The ACDs can smoothly bind with mRNA to form ACDs@mRNA nanocomplexes, and the fluorescent properties of the ACDs afforded the nanoparticles with bio-imaging ability. By screening of the ACDs, O12-Tta-CDs were found to have optimal mRNA transfection efficiency and the ability of spleen-targeted delivery. In addition, O12-Tta-CDs can well transfect the immune cells and promote the maturation and antigen presentation of bone marrow-derived dendritic cells (BMDCs). Furthermore, O12-Tta-CDs@OVA-mRNA was successfully applied to inhibit tumor growth, and more specific T-cell infiltration was observed in spleen and tumors of mice after treatment in the E.G7-OVA tumor model. Besides, O12-Tta-CDs@OVA-mRNA also achieved a good therapeutic effect in tumor recurrence inhibition and tumor prophylactic experiments. This study provided a new direction for the design of mRNA vectors, which is promising in tumor immunotherapy.
研究领域:
生物医学工程
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2021
·
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
·
分子生物学
·
转化医学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Menghua Gao,Jiafeng Zhong,Xinxin Liu,Yanjun Zhao,Dingcheng Zhu,Xiaohuo Shi,Xuehan Xu,Qin Zhou,Wenjing Xuan,Yue Zhang,Yaofeng Zhou,Jianjun Cheng
Organ- and cell-specific delivery of mRNA via modular lipid nanoparticles (LNPs) is promising in treating various diseases, but targeted cargo delivery is still very challenging. Most previous work focuses on screening ionizable and helper lipids to address the above issues. Here, we report the multifacial role of PEGylated lipids in manipulating LNP-mediated delivery of mRNA to the liver. We employed the typical excipients in LNP products, including DLin-MC3-DMA, DPSC, and cholesterol. Five types of PEGylated lipids were selected, and their molar ratio was fixed at 1.5% with a constant PEG molecular weight of 2000 Da. The architecture of steric lipids dramatically affected the in vitro gene transfection, in vivo blood clearance, liver deposition, and targeting of specific cells, all of which were closely linked to the de-PEGylation rate. The fast de-PEGylation resulted in short blood circulation and high accumulation in the liver. However, the ultrafast de-PEGylation enabled the deposition of more LNPs in Kupffer cells other than hepatocytes. Surprisingly, simply changing the terminal groups of PEGylated lipids from methoxyl to carboxyl or amine could dramatically increase the liver delivery of LNPs, which might be associated with the accelerated de-PEGylation rate and enhanced LNP–cell interaction. The current work highlights the importance of manipulating steric lipids in promoting mRNA delivery, offering an alternative approach for formulating and optimizing mRNA LNPs.
研究领域:
分子生物学
·
药物递送
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2010
·
IF 7.365
Yilin Li,Xin Duan,Lihong Jing,Chunhui Yang,Ruirui Qiao,Mingyuan Gao
It was demonstrated that oligonucleotides , independent of their base sequence and length, could effectively induce the cellular uptake of mercapto acid-capped CdTe QDs after the oligonucleotides were covalently attached on the surface of the QDs. Following these experimental observations, a conjugate composed of covalently linked anti-survivin antisense oligonucleotides (ASON) and CdTe QDs was designed and synthesized. Then, the survivin mRNA down-regulation and the apoptosis of HeLa cells induced by ASON were studied. Systematic experimental results revealed that CdTe-ASON could effectively induce the apoptosis of HeLa cells, while CdTe QDs offered the possibility to visualize the specific intracellular localization of the CdTe-ASON probes strongly associated with their biological functions.
研究领域:
分子生物学
·
纳米医学
·
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）