PLZ4@SeD-induced ferroptosis sensitizes bladder cancer to chemotherapy and immunotherapy.

Drug resistance remains a formidable obstacle in the clinical management of solid tumors, including bladder cancer. In this study, building upon our previously developed theranostic platform, we synthesized a streamlined nanoparticle, PLZ4@SeD, which exclusively encapsulates the organoselenium derivative SeD-1b. By focusing on the intrinsic potency of the organic moiety, we explored its potential to overcome therapeutic resistance through metabolic and redox intervention. Our findings demonstrate that PLZ4@SeD is a potent ferroptosis inducer that triggers robust endogenous ROS production and iron mobilization within bladder cancer cells. Mechanistically, PLZ4@SeD activates the oxidative phosphorylation (OXPHOS)-related regulatory axis, which serves as a metabolic engine to fuel mitochondrial ROS generation and drive the ferroptotic cascade. This metabolic rewiring concurrently induces ferroptotic cell death-characterized by GSH depletion and GPX4 downregulation-and suppresses PD-L1 expression. Using bladder cancer cell lines, patient-derived organoids (PDOs), and syngeneic mouse models, we show that this dual-action strategy not only exerts direct cytotoxicity but also significantly enhances the therapeutic efficacy of doxorubicin (DOX) and anti-PD-1 therapy. Furthermore, PLZ4@SeD treatment remodels the tumor microenvironment (TME) by promoting the infiltration of CD4 and CD8 T cells while reducing immunosuppressive F4/80 macrophages, effectively converting "cold" tumors into an immune-responsive "hot" state. In summary, our study provides a compelling mechanistic rationale for utilizing PLZ4@SeD as a novel intervention to overcome multidrug resistance, offering a promising and innovative approach for the precision treatment of bladder cancer.