Cascade-responsive hydrogen sulfide-releasing nanoplatform for synergistic tumor photothermal-immunotherapy

The therapeutic potential of Cu⁺-based chemodynamic therapy (CDT) is significantly limited by its chemical instability, insufficient tumor targeting, and rapid sequestration by intracellular glutathione (GSH). To overcome these challenges, we developed a spatiotemporally responsive nanoplatform, DMOS-Cu₂O@TPP-CS@HA (DCTH), integrating cuproptosis, hydrogen sulfide (H₂S) gas therapy (GT), photothermal therapy (PTT), and immunomodulation. DCTH was composed of a Cu₂O core serving as a Cu⁺ source and near-infrared (NIR) photothermal agent, a triphenylphosphine-functionalized chitosan (TPP-CS) layer for mitochondrial targeting and Cu⁺ stabilization, a GSH-responsive dendritic mesoporous organosilica (DMOS) shell for controlled co-release of H₂S/Cu⁺, and an outer hyaluronic acid (HA) shell facilitating tumor accumulation via CD44-mediated endocytosis. Within the tumor microenvironment (TME), DCTH synchronously released H₂S and Cu⁺, inducing intracellular acidification, inhibiting Cu⁺ efflux (via ATP7A downregulation), enhancing mitochondrial Cu⁺ accumulation, and generating reactive oxygen species (ROS). Consequently, this cascade triggered cuproptosis through dihydrolipoamide S-acetyltransferase (DLAT) inhibition. In vitro, DCTH exhibited efficient tumor cell uptake, mitochondrial localization, selective cytotoxicity, and reversed TME immunosuppression by promoting macrophage repolarization and vascular normalization. In vivo, DCTH showed enhanced tumor targeting, effective photothermal response, significant tumor growth inhibition, immunogenic cell death (ICD) induction, dendritic cell maturation, and increased cytotoxic T-cell infiltration. Overall, DCTH presents a modular and intelligent nanotherapeutic platform leveraging metal-gas synergy to overcome TME-associated therapeutic resistance and achieve multimodal antitumor therapy.