Coordinating the Mechanisms of Action of Ferroptosis and the Photothermal Effect for Cancer Theranostics

Abstract Combination therapy based on different mechanisms of cell death has shown promise in tumor therapy. However, when different modalities are integrated, the maximum synergy of the therapeutic effects is often lacking in the design. Herein, we report a cancer theranostic nanomedicine formula developed by considering the mechanisms of action of ferroptosis and the photothermal effect in combination therapy. The croconaine molecule was encapsulated as both a photothermal converter and an iron‐chelating agent with BSA, thus leading to biocompatible and stable Cro‐Fe@BSA nanoparticles (NPs). The Cro‐Fe@BSA NPs in the tumor milieu showed an activated photothermal effect leading to enhanced radical formation owing to the temperature‐dependent Fenton reaction kinetics, while radical formation during ferroptosis in turn prevented the heat‐induced formation of heat shock proteins and thus the self‐protection mechanism of cancer cells in response to heat. The activatable photoacoustic and magnetic resonance imaging performance of the Cro‐Fe@BSA NPs also enabled safe and reliable cancer theranostics.