Yue Zong,1,2 Jie He,1,2 Yichun Wu,1,2 Jingwen Qin,2 Mingyan Zhao,2 Xingyu Zhu,2 Jun Xie,2 Haitao Yin3 

1Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, Jiangsu, 221009, People’s Republic of China; 2Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, People’s Republic of China; 3The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221112, People’s Republic of China

Correspondence: Haitao Yin; Jun Xie, Email yinhaitao@njmu.edu.cn; xiejun@jsnu.edu.cn

Objective: In this study, a fluorescent magnetic nanomaterial with mitochondrial targeting property (Fe3O4@DPPC@DMPE-PEG2000-LOD@IR780, FDLI) was successfully prepared. We found that FDLI-mediated targeted magnetic hyperthermia (TMH) increases the sensitivity of tumor to radiotherapy (RT). The related underlying mechanisms have also been revealed.
Methods: The crystal structure, chemical composition, magnetic properties, optical characteristics and enzyme-like activity of FDLI were systematically elevated. The mitochondrial targeting ability, anti-tumor efficacy, and RT sensitization potential of FDLI were validated in vitro using breast cancer 4T1 cells. Additionally, a subcutaneous breast tumor transplantation mouse model was established to evaluate the therapeutic effectiveness of FDLI, and an optimized in vivo treatment protocol was assessed. Following intravenous administration of FDLI in mice, the diagnostic and therapeutic effects were evaluated using FDLI-mediated multimodal imaging diagnosis and therapeutic strategies.
Results: Following mitochondrial targeting of tumor cells, FDLI induced localized TMH and exhibited peroxidase-like activity to generate ·OH, which selectively disrupted the mitochondrial membranes of tumor cells, resulting in reduced adenosine triphosphate (ATP) production and elevated lipid peroxidation. Meanwhile, FDLI increased intracellular reactive oxygen species (ROS) levels while reducing glutathione (GSH) levels, thereby promoting ferroptosis in tumor cells and enhancing the sensitivity to synergistic RT.
Conclusion: FDLI can effectively inhibit tumor growth and metastasis, prolonging the survival of tumor-bearing mice through the combined effects of TMH and RT. Our study provides a clinical basis for the development of FDLI as a high-performance agent for integrated tumor diagnosis and therapy.

Keywords: magnetic induction hyperthermia, magnetic nanocrystals, mitochondrial targeting, ferroptosis, radiotherapy sensitisation, synergistic therapy