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

Abstract 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.