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-beta-CD/alpha-CD) and hydrophilic multi-branched polyethyleneimine-ferrocene (PEI-Fc). They are linked by the reactive oxygen species (ROS)-responsive molecular switch beta-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. PCFP@PL/p53 not only responds to reactive oxygen species (ROS) and releases piperlongumine (PL) and ferrocene for Fenton reaction acceleration and ROS enhancement but also induces ferroptosis through a cascade amplifying effect of ROS integrating with p53. The ferroptosis caused by PCFP@PL/p53 activates the anti-tumor immune response, which further strengthens the therapeutic effect based on ferroptosis in triple-negative breast cancer.image

Automated summary

This study constructs cascade bioreactors for the treatment of TNBC by inducing ferroptosis, which activates ROS and p53 to induce cell death and activates the immune system to restrict tumor growth and metastasis.