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The aim of present work is to evaluate the transfection capacity of a new multicomponent system based on dextran (Dex), protamine (Prot), and solid lipid nanoparticles (SLN) after intravenous administration to mice. The vectors containing the pCMS-EGFP plasmid were characterized in terms of particle size and surface charge. In vitro transfection capacity and cell viability were studied in four cell lines, and compared with the transfection capacity of SLN without dextran and protamine. Transfection capacity was related to the endocytosis mechanism: caveolae or clathrin. The Dex–Prot–DNA–SLN vector showed a higher transfection capacity in those cells with a high ratio of activity of clathrin/caveolae-mediated endocytosis. However, the complex prepared without dextran and protamine (DNA–SLN) was more effective in those cells with a high ratio of activity of caveolae/clathrin-mediated endocytosis. The interaction with erythrocytes and the potential hemolytic effect were also checked. The Dex–Prot–DNA–SLN vector showed no agglutination of erythrocytes, probably due to the presence of dextran. After intravenous administration to BALB/c mice, the vector was able to induce the expression of the green fluorescent protein in liver, spleen and lungs, and the protein expression was maintained for at least 7 days. Although additional studies are necessary, this work reveals the promising potential of this new gene delivery system for the treatment of genetic and non-genetic diseases through gene therapy.