H2S-driven Chemotherapy and Mild Photothermal Therapy Induced Mitochondrial Reprogramming to Promote Cuproptosis

Abstract The high level of hydrogen sulfide (H₂S) in colon cancer hinders complete cure with a single therapy. However, excess H₂S also offers a treatment target. A multifunctional cascade bioreactor based on the H₂S-responsive mesoporous Cu₂Cl(OH)₃-loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid to form TPZ@Cu₂Cl(OH)₃-HA (TPZ@CuO) nanoparticles (NPs), demonstrated enhanced efficacy for H₂S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis. The drug was injected through the caudal vein and concentrated in colon cancer through its enhanced permeability, retention effects, and active targeting. The photothermic agent copper sulfide (Cu₉S₈) was prepared in situ by reacting with excess H₂S and near-infrared II, thereby releasing TPZ. When H₂S content was sufficiently depleted, the induction of mitochondrial reprogramming stimulated oxygen consumption by colonic epithelial cells. Activation of the hypoxic prodrug TPZ yielded activated TPZ-ed for chemotherapeutic treatment of colon cancer. Further exacerbation of hypoxia inhibited the synthesis of adenosine triphosphate, leading to decreased expression of heat shock proteins and improving the effectiveness of mild photothermal therapy. Additionally, copper ions were enriched in colon cancer, and Cu²⁺ bound to lipoacylated dihydrolipoamide S-acetyltransferase (DLAT), inducing DLAT heteromerization. The increase in insoluble DLAT led to cytotoxicity and cell death, followed by cuproptosis. Simultaneously, Cu²⁺ generated highly catalytic Cu⁺ under conditions of increased GSH expression, which catalyzed H₂O₂ to produce highly toxic hydroxyl radicals (·OH) during chemodynamic therapy, inducing apoptosis. These results offer a new NP-based treatment modality that can promote copper-related synergistic combination therapy in various ways.