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Adv. Funct. Mater., 07 March 2024 | https://doi.org/10.1002/adfm.202315721 Enhancing CAR-NK Cells Against Solid Tumors Through Chemical and Genetic Fortification with DOTAP-Functionalized Lipid Nanoparticles

Ha Eun Shin¹, Jun-Hyeok Han^1,2, Joo Dong Park¹, Minji Park³, Jieun Han^1,4, Min-Ho Kang⁵, Jung Seung Lee^2,6,7, Chun Gwon Park^2,6,8, Juwon Park⁹, Hyun-Young Kim¹⁰, Duck Cho^3,10, Wooram Park^1,4,7,8

¹Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), Seobu-ro 2066, Jangan-gu, Suwon, Gyeonggi, 16419 Republic of Korea

²Department of Intelligent Precision Healthcare Convergence, SKKU Institute for Convergence, SKKU, Seobu-ro 2066, Jangan-gu, Suwon, Gyeonggi, 16419 Republic of Korea

³Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), SKKU, 115 Irwon-ro, Gangnam-gu, Seoul, 06355 Republic of Korea

⁴Institute of Biotechnology and Bioengineering, College of Biotechnology and Bioengineering, SKKU, Seobu-ro 2066, Suwon, Gyeonggi, 16419 Republic of Korea

⁵Biomedical and Chemical Engineering, Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi, 14662 Republic of Korea

⁶Department of Biomedical Engineering, SKKU, Seobu-ro 2066, Jangan-gu, Suwon, Gyeonggi, 16419 Republic of Korea

⁷Department of MetaBioHealth, SKKU Institute for Convergence, SKKU, Seobu-ro 2066, Jangan-gu, Suwon, Gyeonggi, 16419 Republic of Korea

⁸Korea Institute of Science and Technology (KIST), 5 Hwarang-ro 14-gil, Seongbuk-g, Seoul, 02792 Republic of Korea

⁹Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School Medicine, University of Hawai'i at Manoa, Honolulu, 96813 USA

¹⁰Department of Laboratory Medicine and Genetics, Samsung Medical Center, SKKU School of Medicine, SKKU, 115 Irwon-ro, Gangnam-gu, Seoul, 06351 Republic of Korea

¹¹Department of Biopharmaceutical Convergence, SKKU, Seobu-ro 2066, Jangan-gu, Suwon, Gyeonggi, 16419 Republic of Korea

CORRESPONDING AUTHOR : Wooram Park

Abstract

Natural killer (NK) cells are crucial in the innate immune response and show promise in cancer immunotherapy, but face challenges in activation and targeted gene delivery. In this study, bifunctional lipid nanoparticles (DLNPs) containing 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), designed to bolster the antitumor efficacy of chimeric antigen receptor-modified NK (CAR-NK) cells by facilitating activation and efficient CAR mRNA delivery are introduced. The DLNPs, created by functionalizing FDA-approved LNP compositions, exhibit excellent mRNA encapsulation and colloidal stability. NK cells primed with DLNPs show increased cytotoxicity against cancer cells via extracellular signal-regulated kinase/Mitogen-Activated Protein Kinase pathway modulation and mitochondrial dynamics changes. The DLNPs enter NK cells predominantly through clathrin-mediated endocytosis, boosting mRNA delivery and overcoming NK cells' resistance to genetic manipulation. CAR-NK cells targeting glypican-3, prevalent in hepatocellular carcinoma, show significant therapeutic effects in an orthotopic mouse model. These findings underscore the potential of DLNPs in enhancing CAR-NK cell therapy for solid tumors, marking a significant stride in NK cell-based cancer immunotherapy and broadening prospects for NK cell-related disease interventions.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-20)
연구진국내 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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