Blancafort and colleagues describe a non-viral polymeric system for the delivery of dCas9-KRAB silencers as ribonucleoprotein (RNP) payloads for EWSR1-FLI1 repression. They demonstrate highly efficient RNP delivery and robust silencing of EWSR1-FLI1 in both cell line and patient-derived xenografts of Ewing sarcoma, accompanied by potent anti-tumor effects.