KRAS mutations, present in 95% of pancreatic ductal adenocarcinomas, have historically been considered undruggable. This study demonstrates in vivo CRISPR-Cas9 correction of KRASG12D mutations using lipid nanoparticle delivery in patient-derived xenograft models. Results showed significant tumor regression (67% reduction in tumor volume), improved overall survival, and minimal off-target effects. These findings establish proof-of-concept for CRISPR-based precision oncology in notoriously treatment-resistant cancers.