A Cascade-Activatable Prodrug Nanomedicine for Photothermally Augmented in Situ Synergistic Chemo/Chemodynamic Therapy.

Prodrug nanomedicine represents a promising strategy to enhance tumor-selective drug activation while minimizing systemic toxicity in cancer treatment. Herein, we develop a cascade-activatable prodrug nanoplatform, AuSt@MOS-Cu2O/DSF, constructed by encapsulating Au nanostars (AuSts) within a tetrasulfide bond-rich mesoporous organosilica (MOS) shell co-loaded with disulfiram (DSF) and Cu2O nanoparticles (NPs) for photothermally augmented chemotherapy and chemodynamic therapy. This nanomedicine is designed for sequential activation within the tumor microenvironment (TME). Specifically, glutathione (GSH)-triggered cleavage of the MOS shell releases Cu2O NPs and DSF, followed by a Cu+-mediated Fenton-like reaction in the acidic TME to generate substantial ·OH for chemodynamic therapy. Concurrently, the resulting Cu2+ ions chelate with DSF to form cytotoxic bis(diethyldithiocarbamate)-copper (CuET) in situ, enabling targeted chemotherapy. The system further amplifies therapeutic efficacy through intracellular GSH depletion via the tetrasulfide-rich MOS and Cu2+ as well as near-infrared photothermal effects, collectively enhancing drug release and catalytic activity. In a triple-negative breast cancer murine model, AuSt@MOS-Cu2O/DSF achieves significant tumor growth inhibition with negligible systemic toxicity under near-infrared irradiation. This work presents a synergistic strategy for repurposing clinical drugs into precision nanomedicines for the treatment of aggressive cancers.