An In Situ H₂S-Activated Plasmonic Nanozyme for Near-Infrared II Photo-Thermoelectric Catalytic Therapy

Thermoelectric catalytic therapy represents an emerging therapeutic modality for diverse diseases such as cancer, but faces limitations in efficacy and safety due to low thermoelectric efficiency and systemic toxicity risks. Herein, we report an in situ H₂S-activated plasmonic nanozyme, Cu₂O-HTB@D, fabricated by co-loading Cu₂O nanoparticles and 4-hydroxythiobenzamide (4-HTB) into tetrasulfide-rich dendritic mesoporous organosilica nanoparticles (DMONs) for near-infrared II (NIR-II) plasmonic thermoelectric (PTE) cancer catalytic therapy. Upon accumulation in the tumor microenvironment, the tetrasulfide-rich DMON framework reacts with overexpressed glutathione (GSH), triggering structural disintegration and release of Cu₂O and 4-HTB. Subsequently, H₂S generated from the reaction of DMONs and 4-HTB with GSH induces in situ conversion of Cu₂O into Cu_2-xS. The resulting Cu_2-xS exhibits strong NIR-II plasmonic and PTE properties with peroxidase-, catalase- and oxidase-like multi-enzymatic activities, enabling robust ∙OH and ˙O₂‾ generation amplified by plasmonic hyperthermia and PTE effects under 1064 nm laser irradiation. In vivo studies demonstrate exceptional tumor suppression in a triple-negative breast cancer murine model with high targeting specificity and minimal systemic toxicity after intravenous administration of Cu₂O-HTB@D. This strategy highlights a clinically translatable approach for spatially controlled catalytic therapy via in situ generation of plasmonic nanozymes.