This study aimed to examine the efficacy of a nanocarrier (polyethyleneimine [PEI]-superparamagnetic iron oxide nanoparticle [SPIO]), composed of a core of iron oxide and a shell of PEI, in the systemic delivery of therapeutic siRNA to experimental arthritic joints. PEI-SPIO/siRNA nanoparticles were synthesized and characterized in vitro. Nanoparticles were administered intravenously to arthritic rats to analyze cellular uptake, tissue distribution and the therapeutic effect of a siRNA against the IL-2/-15 receptor β chain (IL-2/IL-15Rβ). PEI-SPIOs loaded with siRNA displayed negligible cytotoxicity, improved siRNA stability, efficient uptake by macrophages and the ability to induce specific gene silencing in vitro. PEI-SPIO-delivered siRNA accumulated easily in inflamed joints and was efficiently taken up by joint macrophages and T cells. Although IL-2/IL-15Rβ siRNA-loaded PEI-SPIOs alone were efficacious in the treatment of experimental arthritis, combination therapy with both PEI-SPIO/IL-2/IL-15Rβ siRNA and a magnetic field displayed an additive anti-inflammatory effect. PEI-functionalized SPIOs can be employed for systemic siRNA delivery in rheumatoid arthritis and enhanced therapeutic benefit can be achieved by the use of an external magnetic field.