Tumor‐Selective Gene Therapy: Using Hairpin DNA Oligonucleotides to Trigger Cleavage of Target RNA by Endogenous flap endonuclease 1 (FEN 1) Highly Expressed in Tumor Cells

Abstract Nucleic acid drugs, which trigger gene silencing by hybridizing with target genes, have shown great potential in targeting those undruggable targets. However, most of the existing nucleic acid drugs are only sequence specific for target genes and lack cellular or tissue selectivity, which challenges their therapeutic safety. Here, the study proposes a tumor cell‐specific gene silencing strategy by using hairpin DNA oligonucleotides to trigger target RNA degrading by highly expressed endogenous flap endonuclease 1 (FEN1) in tumor cells, for selective tumor therapy. Using Kirsten rat sarcoma viral oncogene homolog ( KRAS G12S ) and B‐cell lymphoma 2 ( Bcl‐2) genes as targets, it is verified that the hairpin DNA oligonucleotides show cytotoxicity only to tumor cells but very low effects on normal cells. In addition, hairpin DNA oligonucleotides designed for KRAS inhibition, which are encapsulated in lipid nanoparticles, inhibit tumor growth in mice and demonstrate excellent antitumor efficacy in combination with gefitinib, but has little effect on normal tissues, suggesting that the proposed strategy enables highly selective tumor therapy and has the potential to give rise to a new class of nucleic acid drugs.