7-Dehydrocholesterol Encapsulated Lipid Nanoparticles as a Radiation-activated Radiosensitizer

The pursuit of therapeutics that can be selectively activated by radiation to enhance radiotherapy's efficacy is a pressing need. In this study, we utilized 7-Dehydrocholesterol (7DHC), a biosynthetic precursor of cholesterol, as a lipid targeted radiation-induced radiosensitizer (RIRS) for non-small cell lung cancer (NSCLC). 7DHC, reacting with radiation-induced reactive oxygen species (ROS), initiates a radical chain reaction with polyunsaturated fatty acids (PUFAs) in cell membranes, resulting in direct lipid peroxidation and cell death through ferroptosis. To enhance targeting precision, we incorporated NTS_mut, a ligand for NTSR1 overexpressed in various malignancies, into liposomal nanoparticles. Our tests demonstrate that these NTS_mut-incorporated and 7DHC-loaded liposomal nanoparticles are minimally toxic yet significantly boost radiation efficacy by activating ferroptosis in cancer cells. This induced ferroptosis, serving as a highly immunogenic cell death (ICD) pathway, further amplifies the cancer immune response. This controlled ferroptosis activation strategy presents a promising therapeutic index, paving the way for potential clinical applications.