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윤누리Nuri Yun

지엔티파마

J. Control. Release, Jun 2024, 370 S0168-3659(24)00307-9 | https://doi.org/10.1016/j.jconrel.2024.05.023 Small extracellular vesicle-mediated CRISPR-Cas9 RNP delivery for cardiac-specific genome editing

Dasom Mun ^a, Ji-Young Kang ^a, Hyoeun Kim ^b, Nuri Yun ^c, Boyoung Joung^a

^aDivision of Cardiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea

^bDivision of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea

^cGNTPharma Science and Technology Center for Health, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea

Correspondence to: N. Yun, Boyoung Joung

Abstract

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Although clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) gene editing holds immense potential for genetic manipulation, its clinical application is hindered by the absence of an efficient heart-targeted drug delivery system. Herein, we developed CRISPR-Cas9 ribonucleoprotein (RNP)-loaded extracellular vesicles (EVs) conjugated with cardiac-targeting peptide (T) for precise cardiac-specific genome editing. RNP complexes containing Cas9 and single guide RNA targeting miR-34a, an MI-associated molecular target, were loaded into EVs (EV@RNP). Gene editing by EV@RNP attenuated hydrogen peroxide-induced apoptosis in cardiomyocytes via miR-34a inhibition, evidenced by increased B-cell lymphoma 2 levels, decreased Bcl-2-associated X protein levels, and the cleavage of caspase-3. Additionally, to improve cardiac targeting in vivo, we used click chemistry to form functional T-EV@RNP by conjugating T peptides to EV@RNP. Consequently, T-EV@RNP-mediated miR-34a genome editing might exert a protective effect against MI, reducing apoptosis, ameliorating MI injury, and facilitating the recovery of cardiac function. In conclusion, the genome editing delivery system established by loading CRISPR/Cas9 RNP with cardiac-targeting EVs is a powerful approach for precise and tissue-specific gene therapy for cardiovascular disease.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-19)
연구진국내 연구진
분야 의약학 > 응용의학

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