Small interfering RNA (siRNA) has great potential for the treatment of a variety of inflammatory diseases due to its ability to inhibit the expression of inflammatory genes. However, the clinical potential of siRNA has been limited by drug delivery problems. In this presentation, we present a new delivery vehicle for siRNA composed of polyketal nanoparticles. Polyketals are acid sensitive polymers which are designed to hydrolyze in the acidic environment of the phagosome and osmotically disrupt it. Polyketal-siRNA nanoparticles, targeting TNF-α, were fabricated by an oil in water emulsion method, generating nanoparticles that had average sizes of 800 nm - 900 nm. Cell culture experiments with macrophages demonstrated that polyketal nanoparticles dramatically improved the efficacy of TNF-α siRNA, in 10% serum. In vivo experiments with siRNA polyketal nanoparticles, targeting TNF-α, demonstrated that they were capable of reducing liver toxicity induced by LPS-mediated inflammation. Based on these results, we anticipate numerous applications of polyketal nanoparticles for the delivery of siRNA.