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

mRNA 脂质纳米粒的离子化和结构特性影响其在肌内和血管内给药中的表达。

Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration.

机构信息

Department of Bioengineering, George Mason University, Fairfax, VA, USA.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

出版信息

Commun Biol. 2021 Aug 11;4(1):956. doi: 10.1038/s42003-021-02441-2.

DOI:10.1038/s42003-021-02441-2
PMID:34381159
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8358000/
Abstract

Lipid Nanoparticles (LNPs) are used to deliver siRNA and COVID-19 mRNA vaccines. The main factor known to determine their delivery efficiency is the pKa of the LNP containing an ionizable lipid. Herein, we report a method that can predict the LNP pKa from the structure of the ionizable lipid. We used theoretical, NMR, fluorescent-dye binding, and electrophoretic mobility methods to comprehensively measure protonation of both the ionizable lipid and the formulated LNP. The pKa of the ionizable lipid was 2-3 units higher than the pKa of the LNP primarily due to proton solvation energy differences between the LNP and aqueous medium. We exploited these results to explain a wide range of delivery efficiencies in vitro and in vivo for intramuscular (IM) and intravascular (IV) administration of different ionizable lipids at escalating ionizable lipid-to-mRNA ratios in the LNP. In addition, we determined that more negatively charged LNPs exhibit higher off-target systemic expression of mRNA in the liver following IM administration. This undesirable systemic off-target expression of mRNA-LNP vaccines could be minimized through appropriate design of the ionizable lipid and LNP.

摘要

脂质纳米颗粒（LNPs）被用于递送 siRNA 和 COVID-19 mRNA 疫苗。已知决定其递送效率的主要因素是包含可离子化脂质的 LNP 的 pKa。在此，我们报告了一种可以从可离子化脂质的结构预测 LNP pKa 的方法。我们使用理论、NMR、荧光染料结合和电泳迁移率方法来全面测量可离子化脂质和配方 LNP 的质子化。可离子化脂质的 pKa 比 LNP 的 pKa 高 2-3 个单位，主要是由于 LNP 和水介质之间质子溶剂化能的差异。我们利用这些结果来解释不同可离子化脂质在 LNP 中以递增的可离子化脂质与 mRNA 比进行肌内（IM）和血管内（IV）给药时，体外和体内的广泛递送效率。此外，我们确定在 IM 给药后，带更多负电荷的 LNPs 会导致 mRNA 在肝脏中的非靶向性系统表达增加。通过适当设计可离子化脂质和 LNP，可以最小化 mRNA-LNP 疫苗这种不理想的非靶向性系统 mRNA 表达。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/87a6cbddd7a4/42003_2021_2441_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/ddacbda736d3/42003_2021_2441_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/3f43b010e02f/42003_2021_2441_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/1b91273a21fa/42003_2021_2441_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/f0cfd292d7f8/42003_2021_2441_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/d0af82c2fe5e/42003_2021_2441_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/aeff38a5e5d7/42003_2021_2441_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/87a6cbddd7a4/42003_2021_2441_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/ddacbda736d3/42003_2021_2441_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/3f43b010e02f/42003_2021_2441_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/1b91273a21fa/42003_2021_2441_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/f0cfd292d7f8/42003_2021_2441_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/d0af82c2fe5e/42003_2021_2441_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/aeff38a5e5d7/42003_2021_2441_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/885c/8358000/87a6cbddd7a4/42003_2021_2441_Fig7_HTML.jpg

相似文献

[1]
Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration.

Commun Biol. 2021-8-11

[2]
Amplification of Protein Expression by Self-Amplifying mRNA Delivered in Lipid Nanoparticles Containing a β-Aminoester Ionizable Lipid Correlates with Reduced Innate Immune Activation.

ACS Nano. 2024-10-15

[3]
A fluorinated ionizable lipid improves the mRNA delivery efficiency of lipid nanoparticles.

J Mater Chem B. 2023-5-17

[4]
Iterative Design of Ionizable Lipids for Intramuscular mRNA Delivery.

J Am Chem Soc. 2023-2-1

[5]
On the Formation and Morphology of Lipid Nanoparticles Containing Ionizable Cationic Lipids and siRNA.

ACS Nano. 2018-4-6

[6]
Substituting racemic ionizable lipids with stereopure ionizable lipids can increase mRNA delivery.

J Control Release. 2023-1

[7]
High-Throughput Screening Identifies Differential Influences on mRNA Lipid Nanoparticle Immune Cell Delivery by Administration Route.

ACS Nano. 2024-6-25

[8]
delivery of plasmid DNA by lipid nanoparticles: the influence of ionizable cationic lipids on organ-selective gene expression.

Biomater Sci. 2022-5-31

[9]
Lipid Nanoparticle Formulations for Enhanced Co-delivery of siRNA and mRNA.

Nano Lett. 2018-5-8

[10]
Chemistry of Lipid Nanoparticles for RNA Delivery.

Acc Chem Res. 2022-1-4

引用本文的文献

[1]
Machine Learning and Artificial Intelligence in Nanomedicine.

Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2025

[2]
Advances in Chondroitin Sulfate-Based Nanoplatforms for Biomedical Applications.

Int J Nanomedicine. 2025-8-9

[3]
Nanotechnology-based mRNA vaccines.

Nat Rev Methods Primers. 2023

[4]
Hydroxychloroquine-Derived Ionizable Lipid Facilitates Spleen-Tropic Transfection and Enhances Cancer Immunotherapy.

Chem Bio Eng. 2025-6-18

[5]
Rational design of lipid nanoparticles for enabling gene therapies.

Mol Ther Methods Clin Dev. 2025-6-18

[6]
demonstration of enhanced mRNA delivery by cyclic disulfide-containing lipid nanoparticles for facilitating endosomal escape.

RSC Med Chem. 2025-6-27

[7]
Surface Plasmon Resonance Based Binding Characterization for Screening RNA-Loaded Lipid Nanoparticles (LNPs): Exploring Species Cross-Reactivity in LNP-Apolipoprotein E Interactions.

Mol Pharm. 2025-8-4

[8]
Safflower-Derived Cationic Lipid Nanoparticles: Potential Impact on the Delivery of SARS-CoV-2 MRNA Transcripts.

Arch Razi Inst. 2024-12-31

[9]
Enhancing nucleic acid delivery by the integration of artificial intelligence into lipid nanoparticle formulation.

Front Med Technol. 2025-6-16

[10]
Engineering Lipid-Polymer Nanoparticles for siRNA Delivery to Cancer Cells.

Pharmaceuticals (Basel). 2025-6-10

本文引用的文献

[1]
Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults.

N Engl J Med. 2020-9-29

[2]
Lipid nanoparticle technology for therapeutic gene regulation in the liver.

Adv Drug Deliv Rev. 2020

[3]
Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing.

Nat Commun. 2020-6-26

[4]
A Potent Branched-Tail Lipid Nanoparticle Enables Multiplexed mRNA Delivery and Gene Editing .

Nano Lett. 2020-7-8

[5]
Deconvoluting Lipid Nanoparticle Structure for Messenger RNA Delivery.

Nano Lett. 2020-5-12

[6]
Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing.

Nat Nanotechnol. 2020-4-6

[7]
Efficiency of Chitosan/Hyaluronan-Based mRNA Delivery Systems In Vitro: Influence of Composition and Structure.

J Pharm Sci. 2020-4

[8]
The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs.

Nat Nanotechnol. 2019-12

[9]
Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads.

Nanoscale. 2019-5-9

[10]
A Facile Method for the Removal of dsRNA Contaminant from In Vitro-Transcribed mRNA.

Mol Ther Nucleic Acids. 2019-4-15

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