A ferroptosis nanoplatform for overcoming radioresistance in KRAS-mutant colorectal cancer.

Abstract

KRAS mutations drive poor outcomes in colorectal cancer (CRC), largely by conferring resistance to radiotherapy. In clinical samples, we trace this resistance to an upregulated SLC7A11/GPX4 axis, a defense that shields cancer cells from ferroptosis. Targeting this pathway to re-enable ferroptosis, therefore, represents a rational strategy to restore radiosensitivity. Sulfasalazine (SAS), an FDA-approved drug, inhibits SLC7A11 and induces ferroptosis, but its clinical application is restricted by systemic toxicity and poor tumor accumulation. To bypass these limitations, we develop multifunctional SAS-loaded hafnium oxide nanoparticles (HfO₂@SAS). Ultra-small HfO₂@SAS enables efficient local drug retention and subsequent clearance, minimizing long-term retention risks and supporting favorable biocompatibility. HfO₂@SAS serves a dual function: HfO₂ amplifies radiotherapy via physical radiosensitization through X-ray energy deposition, while SAS disables antioxidant defenses to induce ferroptosis. In KRAS-mutant CRC, this nanoplatform overcomes radioresistance by integrating physical and biochemical mechanisms. Consistent with clinical sample data, we validate the efficacy of HfO₂@SAS in cell and animal levels. Patient-derived organoids provide a human-relevant platform that further supports these findings. Collectively, these findings validate the potential of nanomedicine in combating refractory KRAS-mutant CRC and provide a proof-of-concept for advancing radio-drug combination therapy.