GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE334nnn/GSE334759/primaryOK200Methylation profilingHomo sapiensMethylation profiling by genome tiling arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE334759GEOGSEfalseLocus-selective targeting of the oncogenic fusion EWSR1-FLI1 in Ewing Sarcoma by CRISPR/dCas9 silencers [DNA methylation]Despite the revolutionary impact of genome engineering tools in medicine, the safe and effective intracellular delivery of CRISPR remains a major obstacle for clinical applications. Here, we utilize precision molecular targeting and delivery strategies based on CRISPR/dCas9 systems adapted for epigenetic repression (dCas9-KRAB) to silence oncogenic drivers with high selectivity. As proof-of-principle, we target the EWSR1-FLI1 translocation, which encodes a chimeric and hard-to-drug oncogenic transcription factor driving approximately 85% of the cases of Ewing Sarcoma (EWS)-an aggressive childhood malignancy. We describe the development of a programmable non-viral polymeric system for the delivery of dCas9-KRAB as ribonucleoprotein (RNP) payloads for selective EWSR1-FLI1 repression. We demonstrate highly efficient intracellular delivery of RNPs loaded in polyamide-amine (PAMAM) polymers functionalized by guanidino groups, resulting in robust silencing of EWSR1-FLI1 both in established cell line xenografts and in EWS-related patient-derived xenografts (PDXs) of EWS. We show that silencing of EWSR1–FLI1 is accompanied by potent anti-tumor effects. To our knowledge, this represents the first effective non-viral platform for in vivo delivery of dCas9-KRAB/RNPs, which could be adapted for the repression of any oncogene. We further outline dCas9/RNP formulations for future therapeutic applications to treat poor-prognosis cancers driven by hard-to-drug oncogenes.2026/09/03GSE334759GSM9796729GSM9796728GSM9796727GSM9796733GSM9796732GSM9796731GSM9796730GSM9796735GSM979673433022334759Homo sapiens