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

Abstract 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.