A Ferrocene-Based Supramolecular Photothermal Agent for Enhanced Photothermal/Ferroptosis Therapy and Immune Activation

Photothermal therapy (PTT) is impeded by limited light penetration depth and cellular heat resistance induced by overexpressed heat shock proteins. Herein, we propose a ferrocene (Fc)-based supramolecular photothermal agent (PTA) to improve the therapeutic efficacy. Cy-Fc/CD-PEG not only had excellent photothermal effect but also possessed the ability to induce ferroptosis and immunotherapy. Cy-Fc/CD-PEG released Fc under intracellular acidic conditions. Then the Fe²⁺ of Fc could react with endogenous hydrogen peroxide (H₂O₂) to generate hydroxyl radicals (^•OH) and Fe³⁺. The generated Fe³⁺ could be reduced to Fe²⁺ by depletion of intracellular glutathione (GSH), which promoted reactive oxygen species (ROS) generation via triggering the Fenton reaction and consuming GSH, leading to ferroptosis. Meanwhile, apoptotic tumor cells released abundant tumor-associated antigens, activating antitumor immunity. Both in vitro and in vivo experiments demonstrated excellent antitumor effects by the ferrocene-based Cy-Fc/CD-PEG supramolecular PTA. This work provided a PTT-ferroptosis combination strategy that activated antitumor immunity and inhibited tumor growth.