Abstract: Melanoma is a malignant tumor with a high degree of malignancy. The incidence of melanoma keeps increasing annually. In this study, a melanoma targeted hyaluronic acid (HA) nanogel was synthesized via crosslinking of thiolated HA with terminally functionalized F127-TPGS mixed micelles. Its stability in vitro was evaluated by the average particle size, and the cytotoxicity of the nanogel was investigated by in vitro cell based assays. Next, cell uptake studies were performed to quantitatively and qualitatively investigate the uptake of the nanogels in B16F10 cells. A small sized nanogel with a diameter of 30 nm was synthesized, which was proven to be minimally cytotoxic against both 3T3 or B16F10 cells. Compared with 3T3 cells with low levels of CD44, B16F10 cells with high levels of CD44 showed significantly higher cell uptake efficiency (P<0.05).