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, Jeong Ho Kim, Byoungjae Kong, Sehoon Kim, Sehoon Kim, In-San Kim, Ick Chan Kwon, Yoosoo Yang, Sun Hwa Kim, Sun Hwa Kim
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.