文献检索文档翻译深度研究
Suppr Zotero 插件Zotero 插件
邀请有礼套餐&价格历史记录

新学期,新优惠

限时优惠:9月1日-9月22日

30天高级会员仅需29元

1天体验卡首发特惠仅需5.99元

了解详情
不再提醒
插件&应用
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
高级版
套餐订阅购买积分包
AI 工具
文献检索文档翻译深度研究
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利:CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2025

改善基于细胞外囊泡的 mRNA 递送来治疗家族性高胆固醇血症。

Improved extracellular vesicle-based mRNA delivery for familial hypercholesterolemia treatment.

机构信息

College of Otolaryngology, Head and Neck Surgery, Chinese PLA General Hospital, Beijing 100853, China.

Department of Plastic Surgery, Chinese PLA General Hospital, Beijing, China.

出版信息

Theranostics. 2023 Jun 12;13(10):3467-3479. doi: 10.7150/thno.82873. eCollection 2023.


DOI:10.7150/thno.82873
PMID:37351166
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10283059/
Abstract

Extracellular vesicle (EV)-based low-density lipoprotein receptor () mRNA delivery showed excellent therapeutic effects in treating familial hypercholesterolemia (FH). Nevertheless, the loading inefficiency of EV-based mRNA delivery presents a significant challenge. Recently, RNA-binding proteins (RBPs) have been fused to EV membrane proteins for selectively encapsulating targeted RNAs to promote loading efficiency. However, the strong interaction between therapeutic RNAs and RBPs prevents RNA release from endosomes to the cytosol in the recipient cells. In this study, an improved strategy was developed for efficient encapsulation of mRNA into EVs in donor cells and controllable release in recipient cells. The MS2 bacteriophage coat protein (CD9-MCP) fusion protein, mRNA, and a customized MS2 containing RNA aptamer base-pair matched with mRNA were expressed in donor cells. Cells receiving the above therapeutic EVs were simultaneously treated with EVs containing " releaser" with a sequence similar to the recognition sites in mRNA. Therapeutic effects were analyzed in mice receiving EV treatments via the tail vein. experiments demonstrated improved loading efficiency of mRNA in EVs via MS2-MCP interaction. Treatment of " releaser" competitively interacted with MS2 aptamer with higher affinity and released mRNA from CD9-MCP for efficient translation. When the combinatory EVs were delivered into recipient hepatocytes, the robust LDLR expression afforded therapeutic benefits in mice. We proposed an EV-based mRNA delivery strategy for enhanced encapsulation of therapeutic mRNAs in EVs and RNA release into the cytosol for translation in recipient cells with great potential for gene therapy.

摘要

基于细胞外囊泡(EV)的低密度脂蛋白受体()mRNA 递呈在治疗家族性高胆固醇血症(FH)方面显示出了极好的疗效。然而,基于 EV 的 mRNA 递呈的载药效率不高仍然是一个重大挑战。最近,RNA 结合蛋白(RBPs)已被融合到 EV 膜蛋白上,用于选择性包裹靶向 RNA,以提高载药效率。然而,治疗性 RNA 与 RBPs 之间的强相互作用阻止了 RNA 从受体细胞的内体释放到细胞质中。在本研究中,开发了一种改进的策略,用于在供体细胞中高效包封 mRNA 并在受体细胞中可控释放。在供体细胞中表达了 MS2 噬菌体衣壳蛋白(CD9-MCP)融合蛋白、mRNA 和一种定制的 MS2 ,其中包含与 mRNA 碱基配对的 RNA 适体。同时用含有与 mRNA 识别位点相似序列的“释放剂”处理接收上述治疗性 EV 的细胞。通过尾静脉向接受 EV 治疗的 小鼠进行治疗效果分析。结果表明,通过 MS2-MCP 相互作用,提高了 MS2-MCP 相互作用的 mRNA 在 EV 中的装载效率。“释放剂”竞争性地与具有更高亲和力的 MS2 适体相互作用,并从 CD9-MCP 上释放 mRNA 以进行有效的翻译。当组合 EV 递送至受体肝细胞时,LDLR 的强烈表达为 小鼠提供了治疗益处。我们提出了一种基于 EV 的 mRNA 递呈策略,用于增强治疗性 mRNAs 在 EV 中的包封和 RNA 向细胞质中的释放,以促进受体细胞中的翻译,具有很大的基因治疗潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/590ff79c89c1/thnov13p3467g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/e1e7175434bf/thnov13p3467g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/819d9b33938e/thnov13p3467g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/fe20419092a9/thnov13p3467g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/7b7b6d1fdb8e/thnov13p3467g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/7b306e1185bb/thnov13p3467g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/d90d2477c2f7/thnov13p3467g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/590ff79c89c1/thnov13p3467g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/e1e7175434bf/thnov13p3467g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/819d9b33938e/thnov13p3467g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/fe20419092a9/thnov13p3467g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/7b7b6d1fdb8e/thnov13p3467g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/7b306e1185bb/thnov13p3467g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/d90d2477c2f7/thnov13p3467g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/670f/10283059/590ff79c89c1/thnov13p3467g007.jpg

相似文献

[1]
Improved extracellular vesicle-based mRNA delivery for familial hypercholesterolemia treatment.

Theranostics. 2023

[2]
Exosome-based gene therapy for familial hypercholesterolemia in a mouse model.

Theranostics. 2021

[3]
Selective Encapsulation of Therapeutic mRNA in Engineered Extracellular Vesicles by DNA Aptamer.

Nano Lett. 2021-10-27

[4]
A platform for actively loading cargo RNA to elucidate limiting steps in EV-mediated delivery.

J Extracell Vesicles. 2016-5-13

[5]
"All-in-One" Exosome Engineering Strategy for Effective Therapy of Familial Hypercholesterolemia.

ACS Appl Mater Interfaces. 2022-11-16

[6]
AAV vectors expressing LDLR gain-of-function variants demonstrate increased efficacy in mouse models of familial hypercholesterolemia.

Circ Res. 2014-7-14

[7]
Construction of Fusion Protein for Enhanced Small RNA Loading to Extracellular Vesicles.

Genes (Basel). 2023-1-19

[8]
Low-density lipoprotein receptor-deficient hepatocytes differentiated from induced pluripotent stem cells allow familial hypercholesterolemia modeling, CRISPR/Cas-mediated genetic correction, and productive hepatitis C virus infection.

Stem Cell Res Ther. 2019-7-29

[9]
In Vivo AAV-CRISPR/Cas9-Mediated Gene Editing Ameliorates Atherosclerosis in Familial Hypercholesterolemia.

Circulation. 2019-11-29

[10]
Targeted elimination of senescent cells by engineered extracellular vesicles attenuates atherosclerosis in ApoE mice with minimal side effects.

Theranostics. 2023

引用本文的文献

[1]
Extracellular Vesicles as Precision Delivery Systems for Biopharmaceuticals: Innovations, Challenges, and Therapeutic Potential.

Pharmaceutics. 2025-5-12

[2]
Restoration of TP53 strategy via specific nanoparticles for ovarian cancer therapy.

J Ovarian Res. 2025-5-5

[3]
Revolutionizing mRNA Vaccines Through Innovative Formulation and Delivery Strategies.

Biomolecules. 2025-3-1

[4]
A universal viral capsid protein based one step RNA synthesis and packaging system for rapid and efficient mRNA vaccine development.

Mol Ther. 2025-4-2

[5]
Potential of Exosomes as Multifunctional Nanocarriers for Targeted Drug Delivery.

Mol Biotechnol. 2024-9-13

[6]
From biogenesis to aptasensors: advancements in analysis for tumor-derived extracellular vesicles research.

Theranostics. 2024

[7]
Research progress on the mechanism of exosome-mediated virus infection.

Front Cell Infect Microbiol. 2024

[8]
Recent advances in extracellular vesicles for therapeutic cargo delivery.

Exp Mol Med. 2024-4

[9]
Extracellular vesicles as carriers of mRNA: Opportunities and challenges in diagnosis and treatment.

Theranostics. 2024

[10]
Recent advances in extracellular vesicle engineering and its applications to regenerative medicine.

Biomater Res. 2023-12-11

本文引用的文献

[1]
Unlocking the promise of mRNA therapeutics.

Nat Biotechnol. 2022-11

[2]
Specific interaction of an RNA-binding protein with the 3'-UTR of its target mRNA is critical to oomycete sexual reproduction.

PLoS Pathog. 2021-10

[3]
Selective Encapsulation of Therapeutic mRNA in Engineered Extracellular Vesicles by DNA Aptamer.

Nano Lett. 2021-10-27

[4]
mRNA vaccines for infectious diseases: principles, delivery and clinical translation.

Nat Rev Drug Discov. 2021-11

[5]
Lipid nanoparticles for mRNA delivery.

Nat Rev Mater. 2021

[6]
Exosome-based gene therapy for familial hypercholesterolemia in a mouse model.

Theranostics. 2021

[7]
The RNA binding protein FMR1 controls selective exosomal miRNA cargo loading during inflammation.

J Cell Biol. 2020-10-5

[8]
The RNA-binding protein hnRNPU regulates the sorting of microRNA-30c-5p into large extracellular vesicles.

J Extracell Vesicles. 2020-7-2

[9]
Extracellular vesicles as biomarkers in liver diseases: A clinician's point of view.

J Hepatol. 2020-12

[10]
Systematic Evolution of Ligands by Exosome Enrichment: A Proof-of-Concept Study for Exosome-Based Targeting Peptide Screening.

Adv Biosyst. 2019-2

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

推荐工具

医学文档翻译智能文献检索