A Redox-Responsive Selenium-Containing Nanomedicine Enables Dual Antioxidant System Inhibition to Overcome Platinum Resistance and Enhance Immunotherapy in Bladder Cancer.

Cisplatin-based chemotherapy is the standard first-line treatment for bladder cancer, but its efficacy is limited by drug resistance. Immune checkpoint blockades have emerged as promising therapeutic options; however, their benefits are restricted by the immunosuppressive tumor microenvironment and low response rates. Overcoming both platinum resistance and immune evasion remains a major therapeutic challenge. In this study, we developed NP2, a redox-responsive amphiphilic selenium-containing polymer that encapsulates a platinum(IV) prodrug. NP2 disassembles in response to intracellular glutathione (GSH), releasing active cisplatin to induce DNA damage and apoptosis. Concurrently, diselenide bonds deplete GSH, disturbing the GSH antioxidant system, while selenium residues suppress thioredoxin (Trx) reductase, blocking the Trx system. This dual inhibition prevents cisplatin inactivation, enhances chemotherapy efficacy, and elevates the level of reactive oxygen species (ROS). Therefore, the increased ROS induces immunogenic cell death, promotes dendritic cell maturation, and activates adaptive immunity, thereby converting "immune-cold" tumors into "immune-hot" tumors. Further, NP2 suppressed tumor growth, remodeled the immune microenvironment, and upregulated programmed death-ligand 1 (PD-L1) expression . In combination with the PD-1 monoclonal antibody (αPD-1), NP2 achieved synergistic effects, inhibiting primary tumors and preventing distant progression. NP2 thus represents dual-action nanoparticles that overcome platinum resistance and enhance immunotherapy for bladder cancer.