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

Abstract

AbstractOncogenic 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 RIONmiR‐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. RIONmiR‐143 are nanoparticles of about 70 nm in diameter with improved nuclease resistance under physiological conditions. Moreover, RIONmiR‐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 RIONmiR‐143 is demonstrated in a DLD‐1 cell‐bearing mouse model, with a fourfold decrease in tumor volume compared with NakedmiR‐143. This report presents RIONmiR‐143 as a new option for oncogenic KRAS‐targeting medicine, which can be used as a potent nucleic acid delivery platform.