Efficient Delivery of Antisense Oligonucleotides Using Bioreducible Lipid Nanoparticles In Vitro and In Vivo

Liu Yang; Feihe Ma; Fang Liu; Jinjin Chen; Xuewei Zhao; Qiaobing Xu

doi:10.1016/j.omtn.2020.01.018

Efficient Delivery of Antisense Oligonucleotides Using Bioreducible Lipid Nanoparticles In Vitro and In Vivo

Mol Ther Nucleic Acids. 2020 Mar 6:19:1357-1367. doi: 10.1016/j.omtn.2020.01.018. Epub 2020 Jan 25.

Authors

Liu Yang¹, Feihe Ma¹, Fang Liu¹, Jinjin Chen¹, Xuewei Zhao¹, Qiaobing Xu²

Affiliations

¹ Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA.
² Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA. Electronic address: qiaobing.xu@tufts.edu.

Abstract

The efficient delivery of antisense oligonucleotides (ASOs) to the targeted cells and organs remains a challenge, in particular, in vivo. Here, we investigated the ability of a library of biodegradable lipid nanoparticles (LNPs) in delivering ASO to both cultured human cells and animal models. We first identified three top-performing lipids through in vitro screening using GFP-expressing HEK293 cells. Next, we explored these three candidates for delivering ASO to target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in mice. We found that lipid 306-O12B-3 showed efficiency with the median effective dose (ED₅₀) as low as 0.034 mg·kg^-1, which is a notable improvement over the efficiency reported in the literature. No liver or kidney toxicity was observed with a dose up to 5 mg·kg^-1 of this ASO/LNP formulation. The biodegradable LNPs are efficient and safe in the delivery of ASO and pave the way for clinical translation.

Keywords: PCSK9; antisense oligonucleotide; biodegradable lipid nanoparticle.

Abstract

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