Lee, Jong Won Yoon, Hong Yeol Ko, Young Ji Kim, Eun Hye Song, Sukyung Hue, Seungmi Gupta, Nilaksh Malin, Dmitry Kim, Jay Kong, Byoungjae Kim, Sehoon Kim, In-San Kwon, Ick Chan Yang, Yoosoo Kim, Sun Hwa 2024-08-23T07:00:07Z 2024-08-23T07:00:07Z 2024-08-22 2024-08 1936-0851 https://pubs.kist.re.kr/handle/201004/150475 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 SIRP alpha IgV/anti-CD47 siRNA (vS-siCD47) conjugates that selectively and persistently disrupt the antiphagocytic CD47/SIRP alpha axis in solid tumors. Conjugation of the SIRP alpha IgV domain protein to siRNAs enables tumor dash through CD47-mediated erythrocyte piggyback, primarily blocking the physical interaction between CD47 on cancer cells and SIRP alpha 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. English American Chemical Society Dual-Action Protein-siRNA Conjugates for Targeted Disruption of CD47-Signal Regulatory Protein α Axis in Cancer Therapy Article 10.1021/acsnano.4c06471 1 ACS Nano, v.18, no.33, pp.22298 - 22315 ACS Nano 18 33 22298 22315 N scie scopus 001289108200001 2-s2.0-85200873476 Chemistry, Multidisciplinary Chemistry, Physical Nanoscience & Nanotechnology Materials Science, Multidisciplinary Chemistry Science & Technology - Other Topics Materials Science Article IMMUNE CHECKPOINT BLOCKADE CD47 DELIVERY PHARMACOKINETICS RNA interference siRNA delivery protein-RNAbioconjugate RBC-hitchhiking cancer immunotherapy