Precisely Self-Cooperative Nanoassembly Enables Photothermal/Ferroptosis Synergistic Tumor Eradication

Ferroptosis is identified as a potential target for anticancer therapy. However, most conventional ferroptosis inducers not only fail to trigger intracellular lipid peroxidation storm, but are also prone to cause ferroptosis-related toxicity through off-target destruction of intracellular antioxidant defense systems. Therefore, a potent and highly tumor-specific ferroptosis induction modality is desired. Herein, a self-cooperative nanomedicine for imaging-guided photothermal ferrotherapy, which is fabricated based on molecular nanoassembly (NA) of DiR (a photothermal probe) and ferrocene (Fc, a reactant of the Fenton reaction), is elaborately exploited. DiR-elicited hyperthermia induces both photothermal therapy (PTT) and a significant acceleration of the kinetics of the Fc-involved Fenton reaction, collaboratively causing a lipid peroxidation storm in tumor cells. In turn, plenty of lipid peroxides boost PTT through the downregulation of heat shock protein 90. As expected, such a self-cooperative NA demonstrates synergetic tumor eradication in the 4T1 breast tumor-bearing mice xenograft model. This study offers a novel nanotherapeutic paradigm for precise multimodal cancer therapy.