Cascade Bioreactors Based on Host–Guest Molecular Inclusion Complexes for Triple-Negative Breast Cancer Therapy via Inducing Ferroptosis

Triple-negative breast cancer (TNBC) poses significant challenges in tumor treatment. Ferroptosis, as a novel cell death mechanism, holds promise as a potential therapeutic strategy for TNBC. In this study, cascade bioreactors based on host–guest molecular inclusion complexes (PCFP@PL/p53) are constructed for TNBC therapy via inducing ferroptosis. The bioreactors are composed of hydrophobic hemirotaxane (mPEG-β-CD/α-CD) and hydrophilic multi-branched polyethyleneimine-ferrocene (PEI-Fc). They are linked by the reactive oxygen species (ROS)-responsive molecular switch β-CD@Fc, which can be activated by high levels of ROS. This activation leads to the rapid disassembly of PCFP@PL/p53 and the subsequent release of the loaded piperlongumine (PL) and p53 plasmids. In addition to acting as a “switch,” Fc can react with hydrogen peroxide (H 2 O 2 ) in a Fenton reaction to produce hydroxyl radicals. PL decreases intracellular reduced glutathione and induces H 2 O 2 accumulation, which corporates with Fc to launch ferroptosis and activated p53. The activated p53 disrupts the SLC7A11-GSH-GPX4 pathway, further increasing the intracellular ROS levels, resulting in a cascade amplification of ROS that ultimately induces massive ferroptosis. Meanwhile, the PCFP@PL/p53-induced ferroptosis also activates the immune system in vivo, restricting the growth and metastasis of TNBC, thus providing a novel approach for TNBC therapy based on ferroptosis.