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Adv. Healthc. Mater., Feb 12 2024, | https://doi.org/10.1002/adhm.202303857 Modulating Lipid Nanoparticles with Histidinamide-Conjugated Cholesterol for Improved Intracellular Delivery of mRNA

Onesun Jung¹, Hye-Youn Jung ², Le Thi Thuy ¹, Minyoung Choi ¹, Seongyeon Kim ¹, Hae-Geun Jeon ², Jihyun Yang ², Seok-Min Kim ³, Tae-Don Kim ³, Eunjung Lee ¹, Yoonkyung Kim^2,4, Joon Sig Choi ¹

¹Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, 34134, Republic of Korea.

²Infectious Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.

³Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.

⁴Bioscience Major, KRIBB School, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.

O. Jung, H.-y. Jung, and L. T. contributed equally to this work.

CORRESPONDING AUTHORS : Eunjung Lee, Yoonkyung Kim, Joon Sig Choi

Abstract

Recently, mRNA-based therapeutics, including vaccines, have gained significant attention in the field of gene therapy for treating various diseases. Among the various mRNA delivery vehicles, lipid nanoparticles (LNPs) have emerged as promising vehicles for packaging and delivering mRNA with low immunogenicity. However, while mRNA delivery has several advantages, the delivery efficiency and stability of LNPs remain challenging for mRNA therapy. In this study, an ionizable helper cholesterol analog, 3β[L-histidinamide-carbamoyl] cholesterol (Hchol) lipid was developed and incorporated into LNPs instead of cholesterol to enhance the LNP potency. The pK _a values of the Hchol-LNPs were approximately 6.03 and 6.61 in MC3- and SM102-based lipid formulations. Notably, the Hchol-LNPs significantly improved the delivery efficiency by enhancing the endosomal escape of mRNA. Additionally, the Hchol-LNPs were more effective in a red blood cell (RBC) hemolysis at pH 5.5, indicating a synergistic effect of the protonated imidazole groups of Hchol and cholesterol on endosomal membrane destabilization. Furthermore, mRNA delivery was substantially enhanced in mice treated with Hchol-LNPs. Importantly, LNP-encapsulated SARS-CoV-2 spike mRNA vaccinations induced potent antigen-specific antibodies against SARS-CoV-2. Overall, incorporating Hchol into LNP formulations enables efficient endosomal escape and stability, leading to an mRNA delivery vehicle with a higher delivery efficiency. This article is protected by copyright. All rights reserved.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-14)
연구진국내 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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