Ferroptosis Induction by Fenbendazole Combined With Photothermal Therapy Triggers Dual-Immunotherapy Against Bladder Cancer.

Ferroptosis, a newly recognized form of regulated cell death, has emerged as a promising strategy in cancer therapy. Given the high incidence and recurrence rates of bladder cancer, exploring novel therapeutic approaches is critically important. In this study, we developed a novel intravesical nanoplatform, FBZ@BSA@PDA, that integrates ferroptosis-related oxidative injury immunogenic cell death (ICD) activation, and photothermal therapy (PTT) to achieve synergistic treatment of bladder cancer. The hydrophobic drug fenbendazole (FBZ) was efficiently encapsulated via thermally induced unfolding of bovine serum albumin (BSA), and polydopamine (PDA) was formed by in situ polymerization of dopamine to enhance tissue adhesion and photothermal responsiveness. Following transurethral intravesical administration, the platform enabled sustained drug release and localized PTT. Mechanistically, it induced lipid peroxidation (LPO), GSH depletion, and mitochondrial dysfunction, which suggest that ferroptosis may contribute to tumor cell death. This was accompanied by key ICD markers, including calreticulin (CRT) exposure, high mobility group box 1 (HMGB1) release, and adenosine triphosphate (ATP) secretion, which effectively promoted dendritic cell (DC) maturation and T-cell activation. FBZ@BSA@PDA demonstrated strong anti-tumor efficacy and favorable biosafety in an orthotopic mouse model of bladder cancer. This strategy offers a promising localized immune-potentiated therapeutic approach for clinical bladder cancer treatment.