Boosting ionizable lipid nanoparticle-mediated in vivo mRNA delivery through optimization of lipid amine-head groups

In vitro transcribed messenger RNA (IVT-mRNA) holds great promise for the development of novel therapeutics, such as immunotherapy and vaccination. However, the main obstacle towards clinical translation is the lack of effective delivery systems. Herein, we have synthesized a series of ionizable lip...

Full description

Saved in:
Bibliographic Details
Published in:Biomaterials science 2021-11, Vol.9 (22), p.7534-7546
Main Authors: Ding, Feng, Zhang, Hongqian, Cui, Jiwei, Li, Qiang, Yang, Chuanxu
Format: Article
Language:English
Subjects:
Alkyl acrylates
Biocompatibility
Gene expression
Lipids
Liver
Nanoparticles
Optimization
Protein expression
Proteins
System effectiveness
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In vitro transcribed messenger RNA (IVT-mRNA) holds great promise for the development of novel therapeutics, such as immunotherapy and vaccination. However, the main obstacle towards clinical translation is the lack of effective delivery systems. Herein, we have synthesized a series of ionizable lipids by the addition of an alkyl-acrylate to amine-containing molecules (amine-head groups) as a key component of ionizable lipid nanoparticles (iLNPs) and thoroughly investigated the impact of the amine-head group on the transfection efficiency of iLNPs/mRNA lipoplexes both in vitro and in vivo . The top-performing iLNP (114-iLNP), composed of a lipid with spermine as the amine-head, demonstrated the strongest cellular uptake, membrane disruption and endosomal escape, and further achieved the highest protein expression in HeLa cells with more than 95% transfection efficiency. More importantly, intravenous injection of luciferase mRNA loaded 114-iLNP enables the most efficacious in vivo protein expression, predominantly in the liver. Biodistribution and biosafety evaluation of 114-iLNP/mRNA further demonstrated the liver-selective delivery capability and high biocompatibility. In addition, 114-iLNP facilitated efficient in vivo delivery of a therapeutic gene, human erythropoietin (hEPO) mRNA, and induced hEPO expression in a dose-dependent manner. Therefore, these results demonstrate that the amine-head group in the ionizable lipid significantly affects mRNA delivery efficacy and the leading candidate 114-iLNP composed of a lipid with spermine as the amine-head has great potential for mRNA therapeutics development.
ISSN:2047-4830
2047-4849
DOI:10.1039/d1bm00866h