Dual-Action Protein-siRNA\nConjugates for Targeted\nDisruption of CD47-Signal Regulatory Protein α Axis in Cancer\nTherapy

A series of successes in RNA interference (RNAi) therapies\nfor\nliver diseases using lipid nanoparticles and <i>N</i>-acetylgalactosamine\nhave heralded a current era of RNA therapeutics. However, alternative\ndelivery strategies are required to take RNAi out of the comfort zone\nof hepatocytes. Here we report SIRPα IgV/anti-CD47 siRNA (vS-siCD47)\nconjugates that selectively and persistently disrupt the antiphagocytic\nCD47/SIRPα axis in solid tumors. Conjugation of the SIRPα\nIgV domain protein to siRNAs enables tumor dash through CD47-mediated\nerythrocyte piggyback, primarily blocking the physical interaction\nbetween CD47 on cancer cells and SIRPα on phagocytes. After\ninternalization of the vS-siCD47 conjugates within cancer cells, the\ndetached free-standing anti-CD47 siRNAs subsequently attack CD47 through\nthe RNAi mechanism. The dual-action approach of the vS-siCD47 conjugate\neffectively overcomes the “don’t eat me” barrier\nand stimulates phagocyte-mediated tumor destruction, demonstrating\na highly selective and potent CD47-blocking immunotherapy. This delivery\nstrategy, employing IgV domain protein–siRNA conjugates with\na dual mode of target suppression, holds promise for expanding RNAi\napplications beyond hepatocytes and advancing RNAi-based cancer immunotherapies\nfor solid tumors.