Abstract: This study was aimed to prepare sheddable PEG modified miRNA-complexing nanoparticles and investigate in vitro cellular uptake effect and in vivo distribution profile. The sheddable PEG material was synthesized through condensation. The sheddable PEG modified miRNA-complexing nanoparticles were successfully prepared by electrostatic interaction between gene vector and miRNA, and then ibuprofen was added to deshield PEG layer. The in vitro cellular uptake effect and in vivo distribution profile of nanoparticles were investigated on 4T1 model cells. As a result, the particle size of nanoparticles was 107. 7 nm and Zeta potential was 15. 8 mV. Compared to unsheddable PEG group, the cellular uptake effect by 4T1 tumor cells as well as the concentration on tumor regions was significantly improved in the sheddable PEG group. Results showed that this systen has a great potential application in the field of tumor treatment.