The practical use of quantum dots (QD) as diagnostic, visualizing and therapeutic nano-agents depends on the understanding of fundamental mechanisms of their entrance and trafficking within cells. Here we show that CdSe/ZnS carboxylic-coated QD (COOH-QD) enter fibroblast cells via lipid raft/caveolin-mediated endocytosis, pass early sorting endosomes and accumulate in the multivesicular bodies, but not in the lysosomes. Later phase of their endocytosis leads to the generation of lipid raft/caveolin-dependent endocytosis inhibition that prevents intracellular uptake of new COOH-QD, but not the QD coupled with platelet-derived growth factor BB (PDGF-QD). PDGF-QD enter fibroblasts by the clathrin-mediated endocytosis and undergo similar intracellular trafficking as COOH-QD, yet they accumulate in lysosomes in contrast to COOH-QD. The PDGF-QD activate PDGF receptor-beta and are mitogenic, however, COOH-QD suppress cell migration and chemotaxis. Data show that surface coating of QD with the biologically active proteins redirects their intracellular traffic routes and changes their biological activity.