Dual-Action Protein-siRNA Conjugates for Targeted Disruption of CD47-Signal Regulatory Protein α Axis in Cancer Therapy

Jong Won Lee; Hong Yeol Yoon; Young Ji Ko; Eun Hye Kim; Sukyung Song; Seungmi Hue; Nilaksh Gupta; Dmitry Malin; Jay Kim; Byoungjae Kong; Sehoon Kim; In-San Kim; Ick Chan Kwon; Yoosoo Yang; Sun Hwa Kim

doi:10.1021/acsnano.4c06471

journal article·2024-08-20

Dual-Action Protein-siRNA Conjugates for Targeted Disruption of CD47-Signal Regulatory Protein α Axis in Cancer Therapy

Jong Won Lee, Hong Yeol Yoon, Young Ji Ko, Eun Hye Kim, Sukyung Song, Seungmi Hue, Nilaksh Gupta, Dmitry Malin, Jay Kim, Byoungjae Kong, Sehoon Kim, In-San Kim, Ick Chan Kwon, Yoosoo Yang, Sun Hwa Kim

ACS Nano· Volume 18· Issue 33

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Source abstract

Abstract

-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.

Source: openalex_inverted_index · Quality: baseline

Research context

OpenAlex topics: Phagocytosis and Immune Regulation · RNA Interference and Gene Delivery · Erythrocyte Function and Pathophysiology

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

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

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

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

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

K2B Therapeutics, Cambridge, Massachusetts 02139, United States

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

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

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

Funding

KU-KIST Graduate School of Converging Science and Technology · Korea Institute of Science and Technology

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