Small interfering RNA (siRNA) is potent and highly specific for gene silencing. However, for therapeutic applications, delivery systems are required to protect siRNA from degradation, to enhance cellular uptake and for site-specific delivery. We used a double emulsion technique to encapsulate siRNA into stealth liposomes (SL) to increase entrapment efficiency compared to passive encapsulation. SL are designed for localized, active release of siRNA by secretory phosholipase A2 (sPLA2). sPLA2 acts as a site-specific enzymatic trigger that actively degrades the liposomal carrier in inflamed tissue releasing entrapped drug. Relatively good encapsulation efficiencies compared to passive encapsulation were demonstrated (7–9%) and SL size was appropriate for i.v. administration (60–90 nm). siRNA targeting enhanced green fluorescent protein (EGFP) entrapped in SL did not silence gene expression of HeLa-cells stably expressing EGFP. However, preliminary flow cytometry and confocal microscopy data showed that the SL siRNA formulation increased uptake of siRNA into vesicular compartments of HeLa-cells in a concentration-dependent manner that could be augmented by exogenuos sPLA2. We hypothesize that the SL can be used to target siRNA to inflammed tissue for silencing of cytokine expression in rheumatoid arthritis.