A tetrasulfide bond-bridged mesoporous organosilica-based nanoplatform for triple-enhanced chemodynamic therapy combined with chemotherapy and H2S therapy†

The high glutathione (GSH) concentration and insufficient H₂O₂ content in tumor cells strongly constrict the efficacy of Fenton reaction-based chemodynamic therapy (CDT). Despite numerous efforts, it still remains a formidable challenge for achieving satisfactory efficacy using CDT alone. Herein, an intelligent tetrasulfide bond-bridged mesoporous organosilica-based nanoplatform that integrates GSH-depletion, H₂S generation, self-supplied H₂O₂, co-delivery of doxorubicin (DOX) and Fenton reagent Fe²⁺ is presented for synergistic triple-enhanced CDT/chemotherapy/H₂S therapy. Because the tetrasulfide bond is sensitive to GSH, the nanoplatform can effectively consume GSH, leading to ROS accumulation and H₂S generation in the GSH-overexpressed tumor microenvironment. Meanwhile, tetrasulfide bond-induced GSH-depletion triggers the degradation of nanoparticles and the release of DOX and Fe²⁺. Immediately, Fe²⁺ catalyzes endogenous H₂O₂ to highly toxic hydroxyl radicals (˙OH) for CDT, and H₂S induces mitochondria injury and causes energy deficiency. Of note, H₂S can also decrease the decomposition of H₂O₂ to augment CDT by downregulating catalase. DOX elicits chemotherapy and promotes H₂O₂ production to provide a sufficient substrate for enhanced CDT. Importantly, the GSH depletion significantly weakens the scavenging effect on the produced ˙OH, guaranteeing the enhanced and highly efficient CDT. Based on the synergistic effect of triple-augmented CDT, H₂S therapy and DOX-mediated chemotherapy, the treatment with this nanoplatform gives rise to a superior antitumor outcome.