Lipid Droplets‐Targeted Thermally Activated Delayed Fluorescence Photosensitizer for Photodynamic Therapy‐Mediated Ferroptosis: a New Strategy for Tumor Radiosensitization

Abstract Radiotherapy (RT) is a fundamental modality in cancer treatment, yet its clinical effectiveness is often limited by the development of tumor radioresistance. Significant lipid droplet (LD) accumulation is identified in radioresistant A549 lung cancer cells, suggesting LDs as a potential therapeutic target. To exploit this, a novel lipid droplet‐targeting photodynamic therapy (PDT) strategy is developed to induce LD breakdown and ferroptosis, thereby overcoming radioresistance. Specifically, NIOH‐Cz, a photosensitizer based on a thermally activated delayed fluorescence (TADF) scaffold, is designed. NIOH‐Cz features a small singlet–triplet energy gap (Δ E ST = 0.05 eV) and long‐lived triplet states, enabling efficient type I reactive oxygen species (ROS) generation under white light irradiation. Its optimized lipophilicity (ClogP = 5.75) facilitates selective accumulation in LDs of radioresistant cells. Upon light activation, NIOH‐Cz produces localized ROS in LDs, inducing LD breakdown, lipid peroxidation, ferroptosis, and inhibition of DNA damage repair, thereby enhancing RT sensitivity both in vitro and in vivo. This study demonstrates that LD‐targeted PDT‐induced ferroptosis serves as an effective radiosensitization strategy by exploiting lipid metabolism dependencies, providing insights for the development of next‐generation radiosensitizers.