核糖核酸
体内
生物
核糖核酸酶P
体外
信使核糖核酸
生物物理学
细胞生物学
分子生物学
生物化学
基因
生物技术
作者
Anna K. Blakney,Paul F. McKay,Bárbara Ibarzo Yus,Yoann Aldon,Robin J. Shattock
出处
期刊:Gene Therapy
[Springer Nature]
日期:2019-07-12
卷期号:26 (9): 363-372
被引量:138
标识
DOI:10.1038/s41434-019-0095-2
摘要
Self-amplifying RNA (saRNA) is a promising biotherapeutic tool that has been used as a vaccine against both infectious diseases and cancer. saRNA has been shown to induce protein expression for up to 60 days and elicit immune responses with lower dosing than messenger RNA (mRNA). Because saRNA is a large (~9500 nt), negatively charged molecule, it requires a delivery vehicle for efficient cellular uptake and degradation protection. Lipid nanoparticles (LNPs) have been widely used for RNA formulations, where the prevailing paradigm is to encapsulate RNA within the particle, including the first FDA-approved small-interfering siRNA therapy. Here, we compared LNP formulations with cationic and ionizable lipids with saRNA either on the interior or exterior of the particle. We show that LNPs formulated with cationic lipids protect saRNA from RNAse degradation, even when it is adsorbed to the surface. Furthermore, cationic LNPs deliver saRNA equivalently to particles formulated with saRNA encapsulated in an ionizable lipid particle, both in vitro and in vivo. Finally, we show that cationic and ionizable LNP formulations induce equivalent antibodies against HIV-1 Env gp140 as a model antigen. These studies establish formulating saRNA on the surface of cationic LNPs as an alternative to the paradigm of encapsulating RNA.
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