A novel reactive oxygen species nano-amplifier for tumor-targeted photoacoustic imaging and synergistic therapy

Intracellular redox homeostasis and the type of exogenous Fenton reagent play crucial roles in determining the efficacy of chemodynamic therapy (CDT). Herein, we succeeded for the first time in preparing ultrasmall copper sulfide (CuS) nanodots (1–2 nm)-embedded hollow mesoporous organosilica nanoparticle (HMON), which served as an ideal nanocarrier to load both 3-amino-1,2,4-triazole (3-AT) and disulfiram (DSF) after folate-polyethylene glycol-silane (FA-PEG-Silane) modification. The as-prepared nanoplatform (3-AT/DSF@CuS/HMON-FA, denoted as ADCuSi-FA) was found to regulate intracellular redox homeostasis once internalized by 4T1 cells, showing rapid glutathione (GSH)-responsive 3-AT, DSF and Cu⁺ ions release. Specifically, 3-AT restrained the endogenous hydrogen peroxide (H₂O₂) consumption by suppressing catalase (CAT) activity, thereby augmenting hydroxyl radical (^[rad]OH) generation via Cu⁺-based Fenton-like reaction. DSF, upon complexation with Cu²⁺, exhibited enhanced chemotherapeutic efficacy, while the by-product Cu⁺ ions further boosted the efficacy of CDT. Additionally, CuS nanodots enabled near-infrared-II (NIR-II) photothermal therapy (PTT) and facilitated photoacoustic (PA) imaging, with the ensuing hyperthermia expediting the CDT process. As expected, the tumor growth was dramatically inhibited with PTT/chemotherapy co-synergized CDT. This work offers an innovative paradigm for cooperative cancer treatment as well as new insights into the fabrication of biodegradable inorganic/organic hybrid materials.