양유수 (한국과학기술연구원(KIST))

한빛사논문

조회266

양유수Yoosoo Yang

한국과학기술연구원(KIST)

CV File 275 kb

ACS Nano, Aug 08 2024, | https://doi.org/10.1021/acsnano.4c06471 Dual-Action Protein-siRNA Conjugates for Targeted Disruption of CD47-Signal Regulatory Protein α Axis in Cancer Therapy

Jong Won Lee ^1,2, Hong Yeol Yoon ^2,3, Young Ji Ko ², Eun Hye Kim^2,4, Sukyung Song ⁵, Seungmi Hue ^1,2, Nilaksh Gupta ⁶, Dmitry Malin ⁶, Jay Kim ⁶, Byoungjae Kong ^7,8, Sehoon Kim ^1,9, In-San Kim ^1,9, Ick Chan Kwon ^1,2, Yoosoo Yang ^2,3, Sun Hwa Kim ^1,2

¹KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.

²Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.

³Division of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Hwarang-ro14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.

⁴Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea.

⁵College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.

⁶K2B Therapeutics, Cambridge, Massachusetts 02139, United States.

⁷Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States.

⁸Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States.

⁹Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.

Corresponding Authors : Sun Hwa Kim, Yoosoo Yang

Abstract

A series of successes in RNA interference (RNAi) therapies for liver diseases using lipid nanoparticles and N-acetylgalactosamine have heralded a current era of RNA therapeutics. However, alternative delivery strategies are required to take RNAi out of the comfort zone of hepatocytes. Here we report SIRPα IgV/anti-CD47 siRNA (vS-siCD47) conjugates that selectively and persistently disrupt the antiphagocytic CD47/SIRPα axis in solid tumors. Conjugation of the SIRPα IgV domain protein to siRNAs enables tumor dash through CD47-mediated erythrocyte piggyback, primarily blocking the physical interaction between CD47 on cancer cells and SIRPα on phagocytes. After internalization of the vS-siCD47 conjugates within cancer cells, the detached free-standing anti-CD47 siRNAs subsequently attack CD47 through the RNAi mechanism. The dual-action approach of the vS-siCD47 conjugate effectively overcomes the "don't eat me" barrier and stimulates phagocyte-mediated tumor destruction, demonstrating a highly selective and potent CD47-blocking immunotherapy. This delivery strategy, employing IgV domain protein-siRNA conjugates with a dual mode of target suppression, holds promise for expanding RNAi applications beyond hepatocytes and advancing RNAi-based cancer immunotherapies for solid tumors.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-09)
연구진국내 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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