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

ABSTRACT 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‐Cu ₂ O/DSF, constructed by encapsulating Au nanostars (AuSts) within a tetrasulfide bond‐rich mesoporous organosilica (MOS) shell co‐loaded with disulfiram (DSF) and Cu ₂ O 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 Cu ₂ O 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 Cu ²⁺ 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 Cu ²⁺ as well as near‐infrared photothermal effects, collectively enhancing drug release and catalytic activity. In a triple‐negative breast cancer murine model, AuSt@MOS‐Cu ₂ O/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.