In recent years, organic-inorganic hybrid nanocarriers are explored for effective drug delivery and preferable disease treatments. In this study, using 5-fluorouracil(5-FU)as electronegative model drug, a new type of organic-inorganic hybrid drug delivery system(LDH/HA-PEG/5-FU)was conceived and manufactured by the adsorption of PEGylated hyaluronic acid(HA-PEG)on the surface of layered double hydroxide(LDH, prepared via hydrothermal method)and the intercalation of 5-FU in the interlamination of LDH via ion exchange strategy. The drug loading amount of LDH/HA-PEG/5-FU achieved as high as 34.2%. LDH, LDH/5-FU and LDH/HA-PEG/5-FU were characterized by FT-IR, XRD, TGA, laser particle size analyzer and SEM. With the benefit of p Hdegradable feature of LDH and enzyme-degradable feature of HA, LDH/HA-PEG/5-FU showed p H-degradable and enzyme-degradable capacity in in vitro drug release. Moreover, the drug carrier LDH/HA-PEG contained biocompatible PEG and tumor-targeted HA, resulting in lower cytotoxicity and better endocytosis compared with LDH in vitro. It was suggested that the organic-inorganic hybrid drug delivery system, which was endowed with the properties of controlled release, low toxicity and tumor-targeting delivery for ameliorative cancer therapy, was advisable and might be applied further to fulfill other treatments. In this study, 5-fluorouracil (5-FU) as electronegative model drug, a new type of organic-inorganic hybrid drug delivery system ( Was conceived and manufactured by the adsorption of PEGylated hyaluronic acid (HA-PEG) on the surface of layered double hydroxide (LDH, prepared via hydrothermal method) and the intercalation of 5-FU in the LDH / 5-FU and LDH / HA-PEG / 5-FU were characterized by FT -IR, XRD, TGA, laser particle size analyzer and SEM. With the benefit of pHdegradable feature of LDH and enzyme-degradable feature of HA, LDH / HA-PEG / 5-FU showed pH-degradable and enzyme-degradable capacity in in vitro drug release. Moreover, the drug carrier LDH / HA-PEG contained biocompatible PEG and tumor-targeted HA, resulting in lowe r was cytotoxicity and better endocytosis compared with LDH in vitro. It was suggested that the organic-inorganic hybrid drug delivery system, which was endowed with the properties of controlled release, low toxicity and tumor-targeting delivery for ameliorative cancer therapy, was advisable and might be applied further to fulfill other treatments.