김정환 (Oregon State University, 영남대학교 약학대학) | 한빛사논문 > 한빛사

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조회414

김정환Jeonghwan Kim

Oregon State University, 영남대학교 약학대학

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Proc. Natl. Acad. Sci. USA, Mar 12 2024, 121 (11) | https://doi.org/10.1073/pnas.2307813120 Thiophene-based lipids for mRNA delivery to pulmonary and retinal tissues

Yulia Eygeris ^{# 1 2}, Mohit Gupta ^{# 1}, Jeonghwan Kim ^{# 1 3}, Antony Jozic ¹, Milan Gautam ¹, Jonas Renner ¹, Dylan Nelson ^{1 2}, Elissa Bloom ¹, Adam Tuttle ², Jonathan Stoddard ⁴, Rene Reynaga ⁴, Martha Neuringer ^{4 5}, Andreas K Lauer ^{4 5}, Renee C Ryals ^{4 5}, Gaurav Sahay ^{1 5 6 *}

¹Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR 97201.

²EnterX Biosciences, Inc., Portland, OR 97214.

³College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.

⁴Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006.

⁵Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR 97239.

⁶Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97201.

^#Contributed equally.
^*Corresponding author: correspondence to Gaurav Sahay

Abstract

Lipid nanoparticles (LNPs) largely rely on ionizable lipids to yield successful nucleic acid delivery via electrostatic disruption of the endosomal membrane. Here, we report the identification and evaluation of ionizable lipids containing a thiophene moiety (Thio-lipids). The Thio-lipids can be readily synthesized via the Gewald reaction, allowing for modular lipid design with functional constituents at various positions of the thiophene ring. Through the rational design of ionizable lipid structure, we prepared 47 Thio-lipids and identified some structural criteria required in Thio-lipids for efficient mRNA (messenger RNA) encapsulation and delivery in vitro and in vivo. Notably, none of the tested lipids have a pH-response profile like traditional ionizable lipids, potentially due to the electron delocalization in the thiophene core. Placement of the tails and localization of the ionizable headgroup in the thiophene core can endow the nanoparticles with the capability to reach various tissues. Using high-throughput formulation and barcoding techniques, we optimized the formulations to select two top lipids- 20b and 29d-and investigated their biodistribution in mice. Lipid 20b enabled LNPs to transfect the liver and spleen, and 29d LNP transfected the lung and spleen. Unexpectedly, LNP with lipid 20b was especially potent in mRNA delivery to the retina with no acute toxicity, leading to the successful delivery to the photoreceptors and retinal pigment epithelium in non-human primates.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-05)
연구진국내+국외 연구진
분야 의약학 > 유전 및 유전체의학

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