Oxygen-boosted fluorinated prodrug hybrid nanoassemblies for bidirectional amplification of breast cancer ferroptosis

Ferroptosis, a novel form of cell death, has emerged as a promising approach in cancer therapy. However, the single ferroptosis inducer was ineffective, and the induction of ferroptosis was severely limited by hypoxia niches in breast cancer. Herein, we develop a disulfide bond-bridging fluorinated doxorubicin (DOX) prodrug, which can facilitate the formation of hybrid nanoassemblies (NAs) with sorafenib (Sor) through a molecular co-assembly strategy. The incorporation of fluorinated side chains enhances the oxygen-carrying capacity of the NAs, successfully reversing the redox offensive and defensive situation caused by the dilemma of hypoxia. The reactive oxygen species (ROS) generation capacity of DOX via nicotinamide adenine dinucleotide oxidase (NOXs) within hypoxic tumors is significantly enhanced due to the presence of fluorinated oxygen-carrying as a catalytic substrate. Furthermore, the depletion of nicotinamide adenine dinucleotide phosphate (NADPH) significantly impairs the synthesis of glutathione (GSH), which collaboratively inhibits GSH production with Sor. As expected, the NAs with bidirectional amplification of ROS production and GSH inhibition displays potent antitumor activity in 4 T1 breast cancer-bearing mice. Together, this study presents a novel nanotherapeutic approach for ferroptosis-driven tumor therapy.