A dual gate-controlled intelligent nanoreactor enables collaborative precise treatment for cancer nanotherapy

Recently, disulfiram (DSF), approved by the FDA as an anti-alcoholic drug, has been proved as an effective antitumor drug after chelating with Cu²⁺. To overcome the shortage of intracellular Cu²⁺, we have constructed a dual gate-controlled intelligent nanoreactor (HA-DSF@HCuS@FePtMn, HDHF) via the ingenious combination of hollow copper sulfide (HCuS) nanoparticles, DSF and FePtMn nanocrystals. HDHF has a NIR-actuated gate and enzyme-actuated gate that could be opened in the hyaluronidase-abundant tumor microenvironment with NIR laser irradiation to trigger drug (DSF/FePtMn) release and synergistic therapy. Moreover, the FePtMn nanocrystals could continuously release Fe²⁺, which could catalyze H₂O₂ into highly cytotoxic hydroxyl radicals (˙OH), triggering chemodynamic therapy (CDT). When exposed to NIR laser, HCuS could collapse and release Cu²⁺, which could immediately chelate with DSF, forming the effective anticancer drug (Cu(DTC)₂) and enabling DSF-based chemotherapy. More importantly, the efficient photothermal therapy (PTT) effect of HCuS could accelerate the FePtMn-based CDT and the release of Cu²⁺/DSF, improving tumor treatment efficiency. Thus, this study represents a distinctive paradigm of a dual gate-controlled intelligent nanoreactor enabled PTT-augmented DSF-based chemotherapy and FePtMn-based CDT for cancer nanotherapy.