Rhein-Mn coordination nanomedicine for peritoneal metastatic colorectal cancer: synergistic mitochondrial targeting, immunogenic cell death, and reverses immunosuppression.

The treatment of peritoneal metastatic colorectal cancer (pmCRC) remains highly challenging because current therapies fail to eradicate minimal residual disease and effectively overcome the immunosuppressive tumor microenvironment (TME). These limitations promote immune evasion and uncontrolled peritoneal dissemination, resulting in a poor prognosis. To address these challenges, we developed a bovine serum albumin-encapsulated rhein-manganese nanomedicine (BRM) using a precisely controlled albumin-assisted assembly strategy. BRM exhibits a uniform spherical morphology, pH-responsive degradation, and markedly improved bioavailability, enabling efficient systemic delivery. Following intraperitoneal administration, BRM selectively accumulates at peritoneal tumor sites in murine pmCRC models through receptor-mediated endocytosis. After cellular uptake, BRM escapes endo/lysosomal compartments and releases its bioactive components intracellularly. The synergistic interaction between rhein and Mn2+ induces a robust burst of reactive oxygen species (ROS), activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mediated immunostimulatory signaling, promotes cancer cell apoptosis, and reprograms the immunosuppressive TME. Consequently, BRM significantly suppresses peritoneal dissemination and ascites formation, prolongs survival, and demonstrates excellent biocompatibility. This study establishes BRM as a promising therapeutic platform for pmCRC and provides a generalizable strategy for amplifying antitumor immunity.