Aseptic loosening is the most common long-term complication of total joint replacement, which is associated with the generation of wear debris. The purpose of this study was to investigate the inhibitory effect of small interfering RNA (siRNA) targeting tumor necrosis factor-alpha (TNF-alpha) on wear debris-induced inflammation. A local delivery of lentivirus-mediated TNF-alpha siRNA into the modified murine air pouch, which was stimulated by polymethylmethacrylate (PMMA) particles, resulted in significant blockage of TNF-alpha both in mRNA and protein levels for up to 4 weeks. In addition, significant down-regulation of interleukin-1 (IL-1) and interleukin-6 (IL-6) was observed in TNF-alpha siRNA-treated pouches. The safety profile of gene therapy was proven by Bioluminescent assay and quantitative fluorescent flux. Histological analysis revealed less inflammatory responses (thinner pouch membrane and decreased cellular infiltration) in TNF-alpha siRNA-treated pouches. These findings suggest that local delivery of TNF-alpha siRNA might be an excellent therapeutic candidate to inhibit particle-induced inflammation. (C) 2008 Elsevier Inc. All rights reserved.