Opposing intracellular redox modulation by a carrier-free diselenide nanosystem integrates antifibrosis and ferroptosis sensitization for fibrotic pancreatic cancer therapy.

Abstract

The excessive fibrosis and immunosuppression characteristic of pancreatic ductal adenocarcinoma (PDAC) necessitate multi-targeted tumor microenvironment (TME) regulation. Multi-functional integration in these platforms raises preparation, stability and biosafety concerns, whereas structurally simple materials that enable equivalent TME modulation provide a streamlined solution. Herein, we report a carrier-free system (C8DSe) constructed solely from diselenide. Iron-free C8DSe effectively induces oxidative stress to trigger ferroptosis in tumor cells, while reversing TGF-β induced NIH-3T3 cells activation through simultaneous targeting of the TGF-β/Smad and antioxidant non-canonical NRF2-ARE pathways. It overcomes activated NIH-3T3 cells-mediated ferroptosis resistance by increasing ferrous ion content, inhibiting antioxidant systems, and promoting lipid peroxidation. In orthotopic fibrotic PDAC models, C8DSe exhibits potent antitumor efficacy through direct cytotoxicity, fibrosis reduction, and immune activation. These findings establish diselenide as multi-target agent for TME regulation, providing a template for single-compound therapies and advancing diselenide-based therapeutics.