Selenium Nanoparticles Selectively Target KRAS G13D to Inhibit Colorectal Cancer

ABSTRACT Despite substantial progress in KRAS‐targeted therapies, specific inhibitors of the KRAS G13D mutant remain unavailable. In a retrospective analysis, we found a notable downregulation of glutathione peroxidase 2 (GPX2) in KRAS G13D‐ mutant colorectal cancer (CRC), which correlated with poor outcomes. We hypothesized that GPX2 acts as a tumor suppressor and that its restoration could render KRAS G13D‐driven tumors vulnerable. In this study, we developed a selenium nanoparticle (SeNPs)‐based nanostrategy to suppress KRAS G13D‐driven tumors by modulating GPX2 expression. SeNPs upregulated GPX2 expression, thereby inhibiting metastasis through the GPX2‐HIF1α‐VEGF axis. Moreover, SeNPs release selenite (SeO 3 2− ) in situ, which interacts with the mutant pocket (residues 13–17) of the KRAS G13D protein. In vivo, this multimodal strategy demonstrated exceptional efficacy. In orthotopic CRC models, SeNPs significantly inhibited primary tumor growth and effectively prevented liver metastasis. In cell‑derived xenograft (CDX) and patient‐derived xenograft (PDX) models, SeNPs achieved tumor inhibition rates of 70% and 61%, respectively. Collectively, this study demonstrates the first‐in‐class therapeutic potential of SeNPs against this recalcitrant KRAS mutant and provides a novel nanoplatform for KRAS G13D‐targeted therapy.