We designed highly efficient StealthTM RNAi targeting human tyrosinase with optimum IC50 in the 10-100 pM range. By silencing tyrosinase in melanocytes, we achieved the reconstruction of an artificial epidermis showing a long term lasting (>30 days) inhibition of melanogenesis. Since skin pigmentation can phenotypically be monitored, the use of StealthTM RNAi against tyrosinase on reconstructed pigmented epidermis is a precious tool for the evaluation of delivery vehicles.