We hypothesize that RNAi of MK2 mediated by synthetic peptide nanoplexes may sensitize p53‐deficient ovarian tumors to DNA damaging chemotherapy and improve treatment outcomes in OC patients receiving frontline platinum/taxane therapy; here, we demonstrate their therapeutic performance in vitro and in orthotopic mouse models of late stage, high‐grade serous OC. This evidence concerns the gene TP53 and ovarian neoplasm.