The high glutathione (GSH) concentration and insufficient H 2 O 2 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, H 2 S generation, self-supplied H 2 O 2 , co-delivery of doxorubicin (DOX) and Fenton reagent Fe 2+ is presented for synergistic triple-enhanced CDT/chemotherapy/H 2 S therapy. Because the tetrasulfide bond is sensitive to GSH, the nanoplatform can effectively consume GSH, leading to ROS accumulation and H 2 S generation in the GSH-overexpressed tumor microenvironment. Meanwhile, tetrasulfide bond-induced GSH-depletion triggers the degradation of nanoparticles and the release of DOX and Fe 2+ . Immediately, Fe 2+ catalyzes endogenous H 2 O 2 to highly toxic hydroxyl radicals (˙OH) for CDT, and H 2 S induces mitochondria injury and causes energy deficiency. Of note, H 2 S can also decrease the decomposition of H 2 O 2 to augment CDT by downregulating catalase. DOX elicits chemotherapy and promotes H 2 O 2 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, H 2 S therapy and DOX-mediated chemotherapy, the treatment with this nanoplatform gives rise to a superior antitumor outcome.