To develop a functional nanosized mucosal drug delivery system, a series of amphiphilic cetirizine-chitosan polymer (CTZ-CSs) were constructed. CTZ-CSs could self-assemble into nanoparticles (NPs) which gradually evolved from irregular aggregates to spherical particles with an increasing substitution degree (DS) in CTZ group. The average particle size of CTZ-CSs-NPs with nano ZS90 Zetasizer varied from 153.92nm to 184.48nm and their zeta potential varied between +19.14mV and +22.93mV. Biocompatibility assay exhibited CTZ-CS-NPs had few adverse effects within a certain concentration range. Cetirizine dihydrochloride(CedH):CTZ-CS-NPs displayed burst and sustained drug release profiles in the presence of lysozyme. CedH showed a burst release during the first 6h, after which the release rate slowed down significantly. The release of CedH totally sustained for 72h. Ex vivo mucosal adhesion indicated CedH:CTZ-CS-NPs were able to prolong the residence time in the entire small intestine mucosa.