Abstract: The aim of this study was to prepare hyaluronic acid-modified dexamethasone-loaded core-shell liponanoparticles and to investigate their physicochemical properties as well as in vitro drug release behavior.Chitosan nanoparticles (CS-NPs) were prepared by ionic gelation,and then the freshly prepared CS-NPs suspension was used to hydrate the dry lipid film to form core-shell liponanoparticles (LCS-NPs).Hyaluronic acid (HA) was conjugated with 1,2-dioleoyl-sn-glycero-3-phosphor-ethanolamine (DOPE) to form HA-DOPE,which was then incubated with LCS-NPs to get HA-modified LCS-NPs (HA-LCS-NPs).The particle size,Zeta potential,morphology,and composition of HA-LCS-NPs were evaluated.In vitro drug release of HA-LCS-NPs was investigated using dexamethasone as the model drug.Encapsulation efficiency and drug loading capacity of dexamethasone loaded HA-LCS-NPs were detected via ultracentrifugation.HA-LCS-NPs exhibited clear core-shell structure as can be seen in the TEM images,average size distribution of which was (189±10.3) nm.The encapsulation efficiency and drug loading capacity of dexamethasone-loaded HA-LCS-NPs were 27.4% and 5.9%,respectively. The cumulative release of dexamethasone from HA-LCS-NPs was less than 40% at 72 h.The core-shell liponanoparticles could be successfully prepared by hydrating dry lipid film with suspension of chitosan nanoparticles,followed by modification with HA-DOPE.Dexamethasone could be successfully encapsulated in the HA-LCS-NPs and exhibited sustained release behavior.