Glutathione‐Triggered Nanodrug Disassembly for Enhanced Combined Ferroptosis and Photodynamic‐Chemotherapy of Tumors

Cancer treatment remains challenging due to tumor heterogeneity, drug resistance, and the complex microenvironment that limits monotherapy efficacy. Herein, we report a glutathione (GSH)-responsive multifunctional nanodrug FeCe6@SKN that is self-assembled from the complex formed by the coordination of the photosensitizer Ce6, the natural anticancer agent Shikonin (SKN), and ferric ions (Fe³⁺). After tail vein injection, FeCe6@SKN can effectively accumulate at the tumor site through the EPR effect and subsequently disassemble by high concentration of GSH, leading to the controlled release of Fe²⁺, Ce6, and SKN. This GSH-triggered disassembly and resulting size reduction not only improve the tissue penetration ability of nanodrugs but also enhance the fluorescence signals as well as the singlet oxygen generation capacity of Ce6, enabling efficient photodynamic therapy (PDT). Shikonin simultaneously triggers cancer cell apoptosis by upregulating the pro-apoptotic protein Bax and downregulating the antiapoptotic protein Bcl-2. More notably, the excessive accumulation of intracellular iron ions induces ferroptosis and further suppress tumor growth. It is evidently demonstrated that this multimodal therapeutic approach that combines ferroptosis, PDT, and chemotherapy significantly reduces the drug dosage and improves the therapeutic efficacy. This work may provide a universal and promising approach for developing intelligent and tumor microenvironment-responsive nanodrugs for effective cancer therapy.