Radiation-induced ferroptosis via liposomal delivery of 7-Dehydrocholesterol

作者：Jianwen Li, Shuyue Zhan, Wei Yang, He Zhang, Xinrui Ma, Fanghui Chen, Amy Li, Pakteema Tong, Fangchao Jiang, Zhengwei Cao, I. Delahunty, Jiayi Wang, Yufei Wu, Zhi Liu, Zibo Li, Yong Teng, Libin Xu, Jin Xie · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03303-3 · 被引用次数：7 · 研究领域：Medicine

Ferroptosis is an emerging cell death mechanism characterized by uncontrolled lipid peroxidation. However, selectively inducing ferroptosis in cancer cells remains a challenge. We explore an approach that enables ferroptosis induction through external radiation. The key component of this technology is 7-dehydrocholesterol (7DHC), a natural biosynthetic precursor of cholesterol. To facilitate delivery, we demonstrate that 7DHC, like cholesterol, can be incorporated into the lipid layer of liposomes. To enhance targeting, we also introduced NTSmut, a ligand for the neurotensin receptor 1 (NTSR1), which is overexpressed in multiple malignancies, into liposomes. Under radiation, 7DHC reacts with radiation-induced reactive oxygen species (ROS), initiating a radical chain reaction with polyunsaturated fatty acids (PUFAs) in cell membranes. This process results in direct lipid peroxidation and subsequent ferroptotic cell death. In vivo studies demonstrate that NTSmut-conjugated, 7DHC-loaded liposomes (N-7DHC-lipos) effectively accumulate in tumors and significantly enhance the efficacy of radiation therapy. While conventional radiosensitizers primarily target DNA and its repair mechanisms, our study introduces a strategy to enhance radiotherapy by specifically activating ferroptosis within the irradiated area, thereby minimizing systemic toxicity. Such a strategy of controlled activation of ferroptosis offers a favorable therapeutic index and potentially opens avenues for clinical a...