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This study focused on the impact in 3T3 fibroblasts of several types of empty and curcumin- and resveratrol-loaded solid lipid nanoparticles (SLN) on cell viability and lipid metabolism in relation to their lipid content and encapsulated drug. SLN, prepared by hot homogenization/ultrasonication, were characterized with respect to size, polydispersity index, and zeta potential. Compritol® 888 ATO at different concentrations (4%, 5%, and 6% wt/wt) was chosen as lipid matrix while Poloxamer 188 (from 2.2% to 3.3% wt/wt) and Transcutol (TRC; 2% or 4%) were added as nanoparticle excipients. Prepared SLN were able to encapsulate high drug amount (encapsulation efficiency percentage of about 97-99%). All empty SLN did not show cytotoxicity (by MTT assay, at 24 h of incubation) in 3T3 cells independently of the lipid and TRC amount, while a viability reduction in the range 5-11% and 12-27% was observed in 3T3 cells treated with curcumin-loaded and resveratrol-loaded SLN, respectively. SLN without TRC did not affect cell lipid metabolism, independently from the lipid content. Empty and loaded SLN formulated with 4% of Compritol and 4% of TRC significantly affected, after 24 h of incubation at the dose of 5 μl/ml, cell polar lipids (phospholipids and free cholesterol) and fatty acid profile, with respect to control cells. Loaded compounds significantly modulated the impact of the corresponding empty formulation on cell lipids. Therefore, the combined impact on lipid metabolism of SLN and loaded drug should be taken in consideration in the evaluation of the toxicity, potential application, and therapeutic effects of new formulations.