Abstract: Mucoinert nanoparticles(mPEG-PLGA-NPs)was prepared to overcome the adhesion of mucus in this study and the cellular uptake of nanoparticles with different physio-chemical properties by human gastric cancer HGC-27 cells was investigated. The muco-inert activity of nanoparticles was evaluated by pig gastric mucin(PM)binding experiments. Cellular uptake of nanoparticles in HGC-27 cells was analyzed by confocal laser scanning microscope and HPLC. The results indicated that mPEG-PLGA-NPs had good mucin-inert activity. The mPEG₂₀₀₀-PLGA-NPs could be rapidly uptaken by HGC-27 cells. The celluar uptake of 10%mPEG₂₀₀₀-PLGA-NPs was 1. 7-2. 0 folds higher than PLGA-NPs and 1. 8-2. 4 folds higher than CS-PLGA-NPs during the same incubation time. The intake of diameter nanoparticles with 400 nm was only 55. 9%-70. 3% of those with 120 nm. mPEG-PLGA-NPs possess hydrophilic and near neutrally-charged surfaces that minimize mucoadhesion. mPEG-PLGA-NPs can quickly penetrate the mucus surrounding HGC-27 cells and be uptaken by cells. mPEG-PLGA-NPs are expected to be used for the treatment of mucinous carcinoma.