Synergistic Effect of Ferroptosis‐Inducing Nanoparticles and X‐Ray Irradiation Combination Therapy

Abstract Ferroptosis, characterized by the induction of cell death via lipid peroxidation, has been actively studied over the last few years and has shown the potential to improve the efficacy of cancer nanomedicine in an iron‐dependent manner. Radiation therapy, a common treatment method, has limitations as a stand‐alone treatment due to radiation resistance and safety as it affects even normal tissues. Although ferroptosis‐inducing drugs help alleviate radiation resistance, there are no safe ferroptosis‐inducing drugs that can be considered for clinical application and are still in the research stage. Here, the effectiveness of combined treatment with radiotherapy with Fe and hyaluronic acid‐based nanoparticles (FHA‐NPs) to directly induce ferroptosis, considering the clinical applications is reported. Through the induction of ferroptosis by FHA‐NPs and apoptosis by X‐ray irradiation, the therapeutic efficiency of cancer is greatly improved both in vitro and in vivo. In addition, Monte Carlo simulations are performed to assess the physical interactions of the X‐rays with the iron‐oxide nanoparticle. The study provides a deeper understanding of the synergistic effect of ferroptosis and X‐ray irradiation combination therapy. Furthermore, the study can serve as a valuable reference for elucidating the role and mechanisms of ferroptosis in radiation therapy.