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

Abstract 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 (H2O2) in a Fenton reaction to produce hydroxyl radicals. PL decreases intracellular reduced glutathione and induces H2O2 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.