Hyaluronic acid-coated Cu/Mn Prussian blue nanocubes amplify cuproptosis and cGAS-STING signaling for synergistic prostate cancer therapy.

Prostate cancer is a prevalent immune-cold malignancy in which hypoxia and glutathione (GSH) enrichment hinder redox-dependent therapies and cuproptosis. A hyaluronic-acid-coated copper-manganese Prussian blue nanomedicine (Cu/Mn-PB@HA) was developed to remodel the tumor microenvironment (TME) and enhance mitochondria-associated cuproptosis. The multivalent Cu/Mn centers enable catalase-like O2 generation, GSH-oxidase-like depletion of GSH, and Fenton-like ·OH production, which together enhance chemodynamic therapy (CDT) and create a favorable window for cuproptosis. In acidic and GSH-rich conditions, copper valence cycling initiates cuproptosis, whereas released Mn2+ enhances CDT and activates the cGAS-STING pathway, thereby promoting dendritic-cell maturation and cytotoxic T-cell responses. The HA shell enables CD44-mediated enrichment, improving tumor accumulation without compromising biosafety. In vitro, the platform elevates ROS, induces mitochondrial depolarization, downregulates HIF-1α, and modulates cuproptosis-related proteins. Concurrently, immunogenic cell-death markers are elevated together with cGAS-STING signaling. In vivo, preferential tumor accumulation and significant tumor inhibition are achieved with favorable serum biochemistry and hepatic/renal histology. By integrating "oxygenation-desensitization-ROS" chemistry with Mn2+- enhanced immune activation, Cu/Mn-PB@HA provides a comprehensive strategy for treating immune-cold solid tumors and serves as a versatile platform for theranostic development.