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• By inhibiting SLC7A11/xCT with the inhibitor sulfasalazine and nanoreactors with tetrasulfide bond (-s-s-s-s-)- as the backbone, tumor cell glutathione synthesis is suppressed and its consumption is promoted. • Decreased glutathione content inhibits GPX4 synthesis, promotes intracellular lipid peroxide accumulation, and induces ferroptosis in tumor cells. • The photosensitizer DVDMS produces ROS under ultrasound, which, together with Fe3+, promotes lipid peroxide generation. • Targeted delivery of USP39 shRNA can efficiently silence USP39 gene expression under ultrasound stimulation, inhibiting cell proliferation and selectively inducing autophagy-dependent ferroptosis. The promotion of cellular ferroptosis through ultrasound (US)-assisted Fenton chemistry has emerged as a promising strategy for tumor therapy. To enhance the therapeutic effect, we designed a GSH-responsive ultrasound-driven nanoreactor for RNA interference (RNAi)-intensified ferroptosis in synergistic sono-chemodynamic therapy. Our nanoreactor comprises Fe3+/tetrasulfide bond (-s-s-s-s-) enriched dendritic organosilica encapsulating USP39 shRNA, along with co-loading of sinophoryrin sodium (DVDMS) and sulfasalazine (SAS). Hyaluronic acid surface functionalization ensures high tumor accumulation for active targeting of tumor cells. Upon internalization into tumor cells, the nanoreactor degrades upon the triggering of intracellular overproduced GSH. Ultrasound-triggered release of DVDMS generates large amounts of ROS, synergizing with Fe-catalyzed Fenton chemistry. The simultaneous depletion of glutathione peroxidase 4 and GSH by SAS and Fe3+ weakens the ROS-scavenging system, leading to tumoral redox dyshomeostasis via oxidative stress amplification. This results in the accumulation of lipid peroxide in tumor cells, efficiently inducing ferroptosis. Additionally, USP39 shRNA effectively silences the expression of the USP39 gene in cells, inhibiting tumor cell proliferation, while promoting ATG5 gene expression to intensify ferroptosis. Our work provides a promising nanoreactor for high-efficiency synergistic tumor therapy via RNAi-intensified ferroptosis, highlighting the potential of sono-chemodynamic therapy in cancer treatment. [ABSTRACT FROM AUTHOR]