Abstract: This study aims to prepare lipid bilayer-coated calcium phosphate core-shell nanoparticles (LCAPNs), which can dissolve in an acidic environment to improve the tumor cell toxicity of antitumor drug. Paclitaxel (PTX) loaded lipid coated calcium phosphate nanoparticles (PTX-LCAPNs) were prepared by thin-film dispersion method. The morphology, particle size and in vitro release behavior were characterized. Meanwhile, the intracellular uptake, intracellular dissolution, cell toxicity of PTX-LCAPNs and intracellular accumulation of PTX were evaluated in human HCC cell line (Huh-7). The results suggested that the mean diameter of the spherical LCAPNs was 124.73±6.41 nm. The PTX-LCAPNs demonstrated little drug leakage in simulated normal physiological conditions, while a rapid release was observed in simulated intracellular condition in vitro. Moreover, the PTX-LCAPNs achieved 1.7 fold improvement in the intracellular PTX concentration leading to 5-fold reduction in half maximal inhibitory concentration (IC₅₀) values of PTX compared with calcium phosphate nanoparticles loaded with PTX (PTX-CAPNs), demonstrating a stronger cancer cell lethality.