A multifunctional nanotheranostic: hyaluronic acid-squalene nanoclusters for radiosensitization, ferroptosis, and Mn/Fe-based dual MR imaging

Ferroptosis, a non-apoptotic form of cell death, has shown promise in overcoming resistance to conventional therapies that rely on apoptosis. The combination of ferroptosis inducers with radiation therapy has the potential to improve therapeutic outcomes. However, radiation therapy (RT) alone often requires additional non-toxic radiosensitizers to enhance its efficacy, as the lack of oxygen in hypoxic tumor regions leads to radioresistance. In this study, we synthesized hyaluronic acid and squalene nanoclusters embedded with manganese ferrite nanoparticles to enhance radiosensitization and ferroptosis induction. The CD44 receptor-based targeting of hyaluronic acid and cytoprotective effect of squalene makes the nanocluster biocompatible. The manganese ions (Mn²⁺) within the ferrite structure enable SHMFs to generate reactive oxygen species upon exposure to ionizing radiation, while the iron ions (Fe²⁺) promote apoptosis and drive the Fenton reaction to induce ferroptosis. Additionally, SHMFs function as dual imaging contrast agents for <i>T</i>1- and <i>T</i>2-weighted magnetic resonance imaging. Cellular studies supported using the ferroptosis inhibitor ferrostatin-1, confirmed the occurrence of ferroptosis. <i>In vivo</i> experiments using a subcutaneous colon cancer model demonstrated that SHMFs significantly enhanced the efficacy of RT, leading to effective tumor cell death. These findings highlight the potential of SHMFs as a novel approach to combining RT with ferroptosis induction for improved cancer therapy.