Oncogenic RAS Networks Suppression: Reversibly Ionic Oligonucleotide‐Based Nanoparticles Caged microRNA‐143 Inhibit KRAS‐Mutated Colon Cancer Growth in Tumor‐Bearing Mice

Abstract

Oncogenic RAS has been a particular focus of attention as a pharmacological target over the last four decades. Tumor-suppressor microRNA-143 (miR-143) silences oncogenic KRAS networks, but it requires a nucleic acid delivery vehicle for clinical application. DNA-or RNA-based nucleic acid structures (NASs) are attractive as vehicles that can form unique sequence-based structures. However, for the biological application of NASs, it is still challenging to create a nanostructure that is stable under physiological conditions by reducing intramolecular repulsion due to negative charges. Here, a novel NAS (named RION miR-143 : reversibly ionic oligonucleotide-based nanoparticles caged miR-143) is created by self-assembly involving hybridization and electrostatic interaction via chemically modified oppositely charged ion oligonucleotides. RION miR-143 are nanoparticles of about 70 nm in diameter with improved nuclease resistance under physiological conditions. Moreover, RION miR-143 inhibit the expression of proteins in KRAS networks and cell growth in a dose-dependent manner in KRAS-mutated DLD-1 cells. The anti-tumor activity of RION miR-143 is demonstrated in a DLD-1 cell-bearing mouse model, with a fourfold decrease in tumor volume compared with Naked miR-143 . This report presents RION miR-143 as a new option for oncogenic KRAS-targeting medicine, which can be used as a potent nucleic acid delivery platform.