In this study we used preformed lipid nanoparticles (LNPs) to modulate ENPP1 activity and STING activation in ovarian cancer cell lines and THP-1 macrophages, respectively. ENPP1 activity was detected in PA-1, Caov-3, and SKOV3 cell lines, and preformed loadable SM-102 LNPs facilitated effective siRNA-mediated ENPP1 knockdown in all three cell lines. Among the tested lines, PA-1 cells exhibited the highest ENPP1 activity, which following siRNA-mediated ENPP1 knockdown, led to an increase in extracellular 2’3’-cGAMP levels. PA-1 cells secreted EVs containing ENPP1, which blunted 2’3’-cGAMP- stimulated cytokine release in THP-1 macrophages. Furthermore, cGAMP delivery to THP-1 macrophages and activation of STING was enhanced by the use of preformed loadable SM-102 LNPs.