摘要A structural conjugate(HOC)of polysaccharide,hyaluronic acid(HA)with different ratios of oleic acid(OA)via cystamine(CYS)linker as a new ocular biomaterial was developed.The HOCs with controlled degrees of substitution of OA(4.6％,8.3％and 12.2％)were synthesized to form self-assembled HA-CYS-OA nanoparticles(HONs,HON1,HON2,HON3).A poorly water-soluble cyclosporine A(CsA)to be used for the treatment of multifactorial dry eye disease(DED)was chosen as model drug.CsA-loaded HONs exhibited improved solution transparency via solubilizing capacity of HON,and increased in vitro drug permeation compared to Restasis?.The physicochemical properties of CsA-loaded HONs such as nano behaviors,solution transparency,drug release,drug permeation and ocular cytocompatibility were highly variable according to the ratios of OA substitution.Interestingly,this CsA-loaded HON1 as optimal ocular nanoformulation showed markedly augmented macrophage polarization into the M2 phenotype,downregulated the expression of proinflammatory cytokines levels in LPS-induced M1 macrophage,and effectively inhibited VEGF-induced endothelial cell proliferation and capillary-like tube formation by the synergistic effect of CsA and HON1 containing OA at the same time.Collectively,the current fatty acid conjugated to HA,named fattigation platform,providing the roles and physicochemical properties via structural features of HA could be a promising co-delivery strategy of drug and fatty acid for DED and other ophthalmic disease treatments.