Rheumatoid arthritis (RA) is a chronic inflammatory immune and lubrication dysfunction disease that causes great damage to the joints. Herein, inspired by the unique biochemistry structure and excellent hydration of chondroitin sulfate (CHI) existing in joint system, one kind of novel polysaccharide nanoparticle lubricant, that is chitosan nanoparticles (CS NPs) grafting CHI (CS-CHI), is synthesized by one-step surface chemistry reaction. CHI with negative charges can form hydration layers on the surface of CS NPs, thus improving the lubricity of nanoparticles. Simultaneously, CS-CHI NPs have effective loading and sustained drug release ability for anti-inflammatory drug diclofenac sodium (DS), along with good biocompatibility. Finally, based on a collagen-induced rat RA model, in vitro animals experimental results indicate that the as-synthesized CS-CHI@DS NPs has obvious inhibitory effects on inflammatory factors and can effectively prevent the damaged cartilage from further destruction.