Ohio State University has received a USD 1.43 million NCI R01 grant to develop an exosome-based RNA nanotechnology platform targeting mutant KRAS in metastatic colorectal cancer — one of oncology's most intractable therapeutic challenges, given that KRAS mutations drive roughly 45% of colorectal cancers and remain largely resistant to direct pharmacological inhibition.
The project, led by principal investigators Piotr Rychahou, Peixuan Guo, and Bin Guo, aims to co-deliver a dCas9-HDAC1 ribonucleoprotein complex, KRAS-targeting siRNA, and small-molecule chemotherapy via engineered exosomes displaying RNA aptamer ligands. The approach combines epigenome editing — using a nuclease-inactive dCas9 fused to histone deacetylase HDAC1 to transcriptionally silence the mutant KRAS promoter — with RNA interference and cytotoxic payload delivery in a single platform. Studies will be conducted in orthotopic and patient-derived xenograft models of colorectal cancer lung metastasis.
Targeting an undruggable driver
Mutant KRAS has resisted conventional drug development for decades, and while covalent inhibitors such as sotorasib and adagrasib have demonstrated activity against the KRAS G12C variant, they address only a subset of KRAS mutations and have shown limited durability. The Ohio State team's epigenome editing strategy bypasses the protein-level targeting problem by silencing transcription at the promoter, a distinct mechanism from both direct KRAS inhibitors and downstream pathway blockers such as MEK inhibitors.
The exosome delivery vehicle is engineered to display RNA nanoparticles carrying EpCAM-targeting aptamers on the surface, intended to restrict cell entry to colorectal cancer cells. Negative zeta potential manipulation of the exosome surface is designed to reduce non-specific binding to healthy tissue, which typically carries negatively charged lipid membranes. Exosomes smaller than 100 nm are selected by ultracentrifugation or size exclusion chromatography to reduce macrophage clearance and improve biodistribution.