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The use of nanoparticle-stabilized nanocapsules for cytosolic siRNA delivery for immunomodulation in vitro and in vivo is reported. These NPSCs deliver siRNA directly to the cytosol of macrophages in vitro with concomitant knockdown of gene expression. In vivo studies showed directed delivery of NPSCs to the spleen, enabling gene silencing of macrophages, with preliminary studies showing 70% gene knockdown at a siRNA dose of 0.28 mg/kg. Significantly, the delivery of siRNA targeting tumor necrosis factor-α efficiently silenced TNF-α expression in LPS-challenged mice, demonstrating efficacy in modulating immune response in an organ-selective manner. This research highlights the potential of the NPSC platform for targeted immunotherapy and further manipulation of the immune system.Nanoparticle-stabilized nanocapsules (NPSCs) are used to deliver TNF-α targeted siRNA for inflammation therapy. NPSC siRNA delivery effectively prevents cytokine production in LPS-stimulated mice.Immunomodulation is an effective strategy to treat a wide range of immune diseases.RNA interference (RNAi) is a safe, specific method for reducing the cytokine expression.Nanocapsules deliver siRNA direct to the cytosol for effective RNAi.Nanocapsules loaded with anti-inflammatory siRNA diminished immune response in mice.Anti-inflammatory NPSCs have potential to ameliorate inflammatory diseases.