JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Kangzeng Wu,Fengwei Xu,Yongchao Dai,Shanshan Jin,Anjie Zheng,Ning Zhang,Yuhong Xu
Lipid nanoparticles (LNPs) used for nonviral gene delivery have achieved significant success, particularly in COVID-19 mRNA vaccines. LNPs are routinely characterized by their particle size, polydispersity, and mRNA loading efficiency. However, the internal structure of these particles has not been specified, despite evidence showing that LNPs can be highly heterogeneous, with variations in lipid composition and preparation methods. How these structural features contributed to mRNA LNP vaccine activities is also unclear. In this study, we prepared LNPs with distinctly different internal structures. They were named the emulsion-like LNPs (eLNPs) and membrane-rich LNPs (mLNPs) respectively and compared with the classic “bleb” structure LNPs (cLNPs). The eLNPs contained higher molar percent of the ionizable lipid and lower molar percent of DSPC and cholesterol. The different lipid organization structures lead to varying mRNA delivery activities in vitro and in vivo. After intramuscular injection, eLNPs remained at the injection site and expressed antigens locally. The resulted immune responses had a very fast onset (higher titer at week 2) and lasted longer and stronger (higher titers at week 8) than other LNPs (cLNPs and mLNPs). We hypothesize that the rapid onset and local expression of antigens by muscle cells in the eLNP groups may be favored by the antigen recognition and presentation process, despite the overall mRNA expression activities was not as high especially in liver and other organ. Our data support that eLNPs are potentially the more suitable delivery system for mRNA vaccine due to their high immunogenicity and low systemic toxicity.
研究领域:
药学
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免疫学
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纳米技术
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疫苗学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 17
·3551
·
IF 4.6
Senhao Hu,Wenjing Wang,Yu Zou,Chunmei Li,Hongyan Zou,Chengzhi Huang,Lei Zhan
The development of low-background, facile, and robust fluorescent nanoprobes for imaging and monitoring of intracellular mRNA changes remains a great challenge. Taking advantage of the high fluorescence quenching efficiency of core-shell gold@polydopamine (Au@PDA) nanocomposites and Ca 2+ -promoting DNA adsorption stability, a simple and universal bioconjugate strategy was designed to a construct fluorescent nanoprobe for highly efficient tumor-related mRNA imaging. The fluorescence of Cy5-labeled DNA was quenched up to 92.38% by the AuNP and PDA via nanometal surface energy transfer (NSET) and photoinduced electron transfer (PET), respectively. TK1 mRNA, a biomarker of tumor growth, initiates hybridization and results in fluorescence recovery, which built the foundation for identifying the expression level changes in living cells. More importantly, three kinds of tumor-related mRNA (TK1 mRNA, GalNAc-T mRNA, and C-myc mRNA) can be detected simultaneously with different fluorophore-modified recognition sequences, which can avoid false positive signals and improve the reliability of cancer diagnostic, holding great promise for cancer diagnosis, prognosis, and therapy.
研究领域:
纳米生物技术
·
分子成像
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癌症诊断
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生物分析化学
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基因表达监测
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Xiaoya Guo,Zhiyu Yang,Zhaopei Guo,Huiyan Lai,Hanyu Meng,Meng Meng,Tong Li,Zhen Li,Jie Chen,Yuanji Feng,Xuan Pang,Huayu Tian,Xuesi Chen
The development of mRNA delivery carriers with innate immune stimulation functions has emerged as a focal point in the field of mRNA vaccines. Nonetheless, the expression of mRNA in specific sites and innate immune stimulation at specific sites are prerequisites for ensuring the safety of mRNA vaccines. Based on the synthetic PEIRs carriers library, this study identifies an innovative mRNA delivery carrier named POctS with the following characteristics: 1) simultaneously possessing high mRNA delivery efficiency and stimulator of interferon genes (STING) stimulation function. 2) Leveraging the distinctive site-specific delivery capabilities of POctS, the expression of mRNA at specific sites and the activation of innate immune responses at designated sites are achieved, minimizing formulation toxicity and maximizing the vaccine performance. 3) Tailoring two types of mRNA vaccines based on POctS according to the immune infiltration status of different types of tumors. Briefly, POctS-loading ovalbumin (OVA) mRNA as a tumor antigen vaccine achieves the prevention and treatment of melanoma in mice. Further, POctS-loading mixed lineage kinase domain-like protein (MLKL) mRNA as an in situ tumor vaccine effectively treats orthotopic pancreatic cancer in mice. This delivery carrier offers a feasible mRNA vaccine-based immunotherapy strategy for various types of tumors.
研究领域:
分子生物学
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免疫学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2025
·
IF 5.7
Lulu Chen,Bicheng Chen,Xiang Su
An abdominal aortic aneurysm (AAA) is a life-threatening vascular condition characterized by the dilation of the abdominal aorta, with ferroptosis playing a significant role in its pathogenesis. This study investigates the therapeutic potential of engineering biomimetic nanovesicles to deliver phosphatidylethanolamine-binding protein 1 (PEBP1) mRNA for inhibiting ferroptosis in vascular smooth muscle cells (VSMCs) and preventing AAA progression. Differential gene expression analysis of the AAA transcriptomic dataset GSE57691 identified 243 differentially expressed genes (DEGs), intersecting with 12 ferroptosis-related genes. Single-cell analysis of dataset GSE237230 highlighted PEBP1 as a key gene in VSMCs. Overexpression of PEBP1 in VSMCs enhanced proliferation, reduced reactive oxygen species (ROS) and iron levels, and inhibited apoptosis and ferroptosis via the NRF2/GPX4 axis. The engineered biomimetic nanovesicles demonstrated significant uptake by VSMCs and effective delivery of PEBP1 mRNA. In vivo studies confirmed that these nanovesicles substantially inhibited AAA progression in mice. This study presents a novel bioengineering approach for AAA treatment by targeting ferroptosis through PEBP1 mRNA delivery, offering a promising molecular strategy for the prevention and management of AAA.
研究领域:
生物医学工程
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纳米技术
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分子生物学
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心血管疾病研究
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基因治疗
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-16
·
IF 9.429
Xing Zhen,Xue Jing,Ma Xindian,Han Congwei,Wang Zhenzhen,Luo Shunhuang,Wang Chunming,Dong Lei,Zhang Junfeng
The formation of biomolecular condensates via liquid‒liquid phase separation (LLPS) is an advantageous strategy for cells to organize their subcellular compartments for diverse functions. Recent findings suggest that RNA or RNA-related LLPS techniques have potential for the development of new cellular regulation strategies. However, manipulating RNA LLPS in living cells has great challenges. Herein, we report that cationic polymers (CPs) have strong RNA LLPS-inducing activity. By introducing CPs into living cells or RNA solutions, significant RNA LLPS was verified through confocal imaging, turbidity assays, and fluorescence recovery after photobleaching (FRAP) tests. Among them, turbidity kinetics determinations indicated that the hydrophilic positively charged amino groups on the CPs play essential roles in RNA phase separation. Moreover, the LLPS induced by the cationic polymers dramatically changed the gene expression patterns in the cells. Interestingly, we found that TGFβ1 mRNA was highly encapsulated in the RNA droplets, which lowered the immunosuppressive capability of the tumor cells and triggered marked antitumor reactions in a mouse breast cancer model. Thus, we present here the CP-based modulation of RNA LLPS as a novel transcriptional manipulation method with potential for cancer immunotherapy drug development. Graphical Abstract
研究领域:
生物物理学
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癌症生物学
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分子生物学
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药学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 11
·2461
·
IF 4.2
Wei He,Xinya Zhang,Yangxiaoyu Zou,Ji Li,Chong Wang,Yucai He,Qiuheng Jin,Jianren Ye
mRNA vaccines are entering a period of rapid development. However, their synthesis is still plagued by challenges related to mRNA impurities and fragments (incomplete mRNA). Most impurities of mRNA products transcribed in vitro are mRNA fragments. Only full-length mRNA transcripts containing both a 5′-cap and a 3′-poly(A) structure are viable for in vivo expression. Therefore, RNA fragments are the primary product-related impurities that significantly hinder mRNA efficacy and must be effectively controlled; these species are believed to originate from either mRNA hydrolysis or premature transcriptional termination. In the manufacturing of commercial mRNA vaccines, T7 RNA polymerase-catalyzed in vitro transcription (IVT) synthesis is a well-established method for synthesizing long RNA transcripts. This study identified a pivotal domain on the T7 RNA polymerase that is associated with erroneous mRNA release. By leveraging the advantageous properties of a T7 RNA polymerase mutant and precisely optimized IVT process parameters, we successfully achieved an mRNA integrity exceeding 91%, thereby further unlocking the immense potential of mRNA therapeutics.
研究领域:
分子生物学
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生物技术
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疫苗学
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2025
·
IF 5.6
Longyu Wang,Yichen Li,Pingge Jiang,Hao Bai,Chengfan Wu,Qi Shuai,Yunfeng Yan
Lipid nanoparticles (LNPs) have shown promising performance in mRNA delivery. Nevertheless, a thorough understanding of the relationship between mRNA delivery efficacy and the structure of LNPs remains imperative. In this study, we systematically investigated the effects of additional hydrophobic amines on the physicochemical properties of mRNA LNPs and their delivery efficacy. The results indicated that this influence depended on the chemical structure of the additional amines and the structure of the lipid carriers. The appropriate addition of the hydrophobic amine 2C8 to lipid carriers with structural 2C8 or 2C6 tails significantly increased their mRNA delivery efficiency. In contrast, the addition of hydrophobic amine C18 to LNPs resulted in a decrease in mRNA delivery efficiency, while the addition of hydrophobic amines 2C6 and C8, as well as alkanes C12' and C16', had relatively little effect on mRNA delivery. Further investigations demonstrated that the appropriate addition of 2C8 could reduce LNP size, moderate internal hydrophobicity and LNP stability, facilitate mRNA release, enhance cellular uptake, and improve intracellular transportation of LNPs, thereby achieving superior mRNA delivery efficiency. These findings highlight the important role of additional hydrophobic amines in mRNA delivery with LNPs and provide valuable insights for the advancement of mRNA delivery carriers.
研究领域:
分子生物学
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药物递送系统
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
RSC Chemical Biology
·
2025
·
IF 3.1
Gang Wang,Mo Li,Peng Zou
Subcellular RNA localization is a conserved mechanism in eukaryotic cells and plays critical roles in diverse physiological processes including cell proliferation, differentiation, and embryo development. Nevertheless, the characterization of centrosome-localized mRNAs remains under-explored due to technical difficulties. In this study, we utilize APEX2-mediated proximity labeling to map centrosome-proximal transcriptome, identifying DLGAP5 mRNA as a novel centrosome-localized transcript during mitosis. Using a combination of drug perturbation, truncation, deletion, and mutagenesis, we demonstrate that microtubule binding of nascent MBD1 polypeptide is required for centrosomal transport of DLGAP5 mRNA. Our data also reveals that mRNA targeting efficiency is tightly linked to the coding sequence (CDS) length. Thus, our study provides a transcriptomic resource for future investigation of centrosome-localized RNAs, and sheds light on mechanisms underlying mRNA centrosomal localization.
研究领域:
细胞生物学
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分子生物学
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转录组学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL GENETICS
·
2020
·Vol. 58
·期 4
·551-565
·
IF 2.027
Xie Shaolin,Zhou Aiguo,Feng Yongyong,Zhang Yue,Li Junyi,Sun Zhuolin,Fan Lanfen,Zou Jixing
Cytochrome P4501A (CYP1A) has been used as a specific biomarker for monitoring water contamination such as PAHs, PCBs and dioxins. In the present study, the cyp1a gene of Gambusia affinis was cloned and sequenced and their expressions under PAHs exposure were characterized. The newly identified cyp1a encodes a protein with 521 amino acids that shared 96–80% identity with other Cyprinodontiformes fishes. RT-PCR analysis revealed that the basal mRNA level of cyp1a was highly expressed in liver and intestine. The expression level of cyp1a was significantly induced by exposure to 100 μg/L 3, 4-Benzopyrene (BaP) for 5 days in the muscle, testis, brain, liver and intestine of adult male fish. Except in the testis, the induced mRNA level of cyp1a ultimately decreased after prolonging the exposure time to 25 days. As for testis, the induced mRNA level of cyp1a was maintained at a high level during the entire exposure time under 100 μg/L BaP exposure. Furthermore, the expression of cyp1a increased with exposure time under a relatively low exposure concentrations 1 μg/L. Regarding the effects of other PAHs, D(a,h)A, BbF, and BaA showed a statistically significant effect of induction on mRNA level of cyp1a in the muscle, testis, brain, liver and intestine.
研究领域:
环境科学
·
分子生物学
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DOI
PubMed
高影响因子
Biomaterials Science
·
2025
·
IF 5.7
Lan Zhang,Ping Chen,Xiao-Li Tian,Yue Hu,Rong Wang,Ji Zhang
As mRNA vaccines continue to gain widespread attention, lipid nanoparticles (LNPs), the preferred platform for mRNA delivery, have become a key focus of development. 1, 4, 7, 10-Tetraazacyclododecane (cyclen), with its excellent protonation capability and ease of modification, has emerged as a promising candidate for the ionizable head group of lipid materials. In this study, a series of cyclen-based lipidoids with different linkages and hydrophobic tails were designed and conveniently synthesized. Structure-activity relationship studies were performed to screen out the carriers capable of efficient mRNA delivery and with potential for tumor therapeutic applications. In vivo biodistribution experiments in mice revealed that the lipidoid OEs-K, containing both hydroxyl and ester groups in its linkage, exhibited not only high mRNA delivery efficiency but also lymph node-targeting properties. Using a subcutaneous EG.7-OVA tumor model in mice, the delivery of tumor antigen OVA mRNA by the lipidoid material was evaluated for its antitumor immunotherapeutic potential. The results demonstrated that LNPs formulated with OEs-K promoted dendritic cell uptake in lymph nodes, effectively activated immune responses, and inhibited tumor growth. Hematological and histopathological evaluations indicated no significant toxicity to the body. This study might provide insights into the design and development of carrier materials for mRNA vaccines.
研究领域:
生物医学工程
·
分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2021
·Vol. 33
·期 34
·2101707
·
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
·
分子生物学
·
药学
·
病毒学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
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
·
药剂学
·
老年医学
·
基因治疗
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线粒体生物学
·
转化医学
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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）