The epidermal growth factor receptor (EGFR) pathway plays an important role in the progression of colorectal cancer (CRC). Anti-EGFR drugs based on antibodies have been widely used for treating CRC through inducing the cell death pathway. However, the majority of CRC patients will inevitably develop drug resistance during anti-EGFR drug treatment, which is mainly caused by point mutation in the KRAS oncogene as single-nucleotide polymorphisms. To address this problem, we developed a nanoliposomal (NL) particle containing a Cas9 nuclease protein and single-guide RNA (sgRNA) complex (Cas9 ribonuclease protein, Cas9-RNP) for genomic editing of the KRAS mutation. The NL particle is composed of a bio-compatible lipid compounds that can effectively encapsulate Cas9-RNP complexes. By modifying the NL particle to include the appropriate antibody, it can specifically recognize EGFR expressing CRC and effectively delivered the gene-editing complexes. The conditions of NL treatment were optimized using a KRAS mutated CRC in vivo mouse model. Mice with KRAS-mutated CRC showed drug resistance against Cetuximab, a therapeutic antibody drug. After treating the mice with the KRAS gene-editing NL particles, the implanted tumors showed a dramatic decrease in size. Our results demonstrated that this genomic editing complex has great potential as a therapeutic carrier system for treating of drug-resistant cancer caused by a point mutation.