Inhalable biomimetic polyunsaturated fatty acid-based nanoreactors for peroxynitrite-augmented ferroptosis potentiate radiotherapy in lung cancer

Abstract

Abstract The limited efficacy and poor tumor accumulation remain crucial challenges for radiotherapy against lung cancer. To address these limitations, we rationally developed a polyunsaturated fatty acid (PUFA)-based nanoreactor (DHA-N@M) camouflaged with macrophage cell membrane to improve tumoral distribution and achieve peroxynitrite-augment ferroptosis for enhanced radiotherapy against lung cancer. After nebulization, the nanoreactors exhibited superior pulmonary accumulation in orthotopic lung cancer-bearing mice, with 70-fold higher than intravenously injected nanoreactors at 12 h post-administration, and distributed deeply in the tumors. DHA-N@M selectively released nitric oxide (NO) in glutathione (GSH)-enriched tumor cells, with consumption of GSH and subsequent inactivation of glutathione peroxidase 4 (GPX4). Under radiation, NO reacted with radiotherapy-induced reactive oxygen species (ROS) to generate peroxynitrite (ONOO-), resulting in redox homeostasis disruption. Combined with docosahexaenoic acid (DHA)-induced lipid metabolism disruption, overwhelming ferroptosis was induced both in vitro and in vivo. Notably, DHA-N@M mediated ferroptosis-radiotherapy significantly suppressed tumor growth with a 93.91% inhibition in orthotopic lung cancer models. Therefore, this design provides a nebulized ferroptosis-radiotherapy strategy for lung cancer.

Keywords

• Radiotherapy
• Ferroptosis
• Lung cancer
• Inhalation
• Nanoreactor