Ferritin-based nanocarrier delivery of KRAS G12D inhibitor in pancreatic adenocarcinoma cells and patient-derived organoids: A novel approach for treatment.

Activating KRAS mutations, particularly G12 variants, are key drivers in pancreatic ductal adenocarcinoma and other cancers. While KRAS was historically considered undruggable, mutant-specific inhibitors, including non-covalent KRAS G12D inhibitor MRTX1133, have emerged. However, efficacy and resistance remain challenges. We utilized a stimuli-sensitive, ferritin-derived nanomedicine platform to encapsulate high concentrations of MRTX1133, aiming for targeted delivery of the drug to KRAS-mutated pancreatic ductal adenocarcinoma cells. This platform, designed for enhanced biodistribution and reduced off-target effects, achieved a major efficacy over free MRTX1133 in 2D models regarding cell proliferation and KRAS inhibition pathway and, in 3D spheroid models, specifically concerning cell death. Efficacy in patient-derived organoids was comparable. This study demonstrates the potential of this nanomedicine platform for targeted delivery of KRAS mutant-specific inhibitors to human tumors.