H₂S-driven chemotherapy and mild photothermal therapy induced mitochondrial reprogramming to promote cuproptosis

The elevated level of hydrogen sulfide (H₂S) in colon cancer hinders complete cure with a single therapy. However, excessive 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 (HA) to form TPZ@Cu₂Cl(OH)₃-HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H₂S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H₂S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu₉S₈) from the TCuH, followed with the release of TPZ. The depletion of H₂S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu²⁺ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H₂O₂ to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy.