HSA-templated synergistic platform boosts radiotherapy via enhanced radiosensitization and ferroptosis induction.

Radiotherapy efficacy in cancer treatment is frequently compromised by tumor radioresistance, limited immune activation, and off-target toxicity. To address these challenges, we developed a multifunctional nanosystem (FPPF@HC), combining FePt-PEG-FA nanoparticles encapsulated in an HSA-CaP hybrid shell. This platform prolongs systemic circulation, effectively targets tumors via the enhanced permeability and retention effect, and facilitates active folate receptor-mediated uptake. In the acidic tumor microenvironment, the nanoparticles release FePt cores, triggering ferroptosis through Fe²⁺-mediated Fenton reactions, oxidative stress, lipid peroxidation, and subsequent tumor cell death. Concurrently, ferroptosis-induced immunogenic cell death enhances dendritic cell maturation and CD8⁺ effector T cell infiltration, remodeling the tumor immune microenvironment. In vitro and in vivo studies demonstrated significantly improved tumor suppression, radiosensitivity, and immune activation compared with radiotherapy alone. Comprehensive biosafety evaluations indicated minimal systemic toxicity. This nanosystem offers a promising strategy for overcoming radioresistance and improving clinical outcomes in cancer therapy.