Carrier-free nanomedicine, Osteosarcoma, Ferroptosis, PDT/PTT Therapy, Reactive oxygen species, Biotechnology, TP248.13-248.65, Medical technology, R855-855.5

Abstract Osteosarcoma treatment remains challenging due to the limitations of single-modality therapies. To address this, we designed a carrier-free nanomedicine SRF@CuSO4.5H2O@IR780 (CSIR) for synergistic ferroptosis, photodynamic therapy (PDT), and photothermal therapy (PTT) in osteosarcoma. Interestingly, CSIR could harness the enhanced permeability and retention (EPR) effect to effectively enter tumors. Copper ions (Cu2+) within CSIR could react with the reductive intracellular environment, depleting glutathione (GSH) levels. Near-infrared (NIR) irradiation of CSIR further depleted GSH through reactive oxygen species (ROS) generation. Additionally, CSIR released sorafenib (SRF), which inhibited cystine-glutamate antiporter system xCT (xCT), thereby blocking GSH biosynthesis. RNA sequencing data confirmed ferroptosis induction by CSIR. This synergistic strategy of GSH depletion-induced ferroptosis, enhanced PDT, and photothermal cascade holds promise for improved osteosarcoma treatment and future nanomedicine design.