Engineered polysaccharide nanocarriers for targeted intra-articular therapy of rheumatoid arthritis: Design principles and translational evidence

Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic synovial inflammation, progressive cartilage destruction, and bone erosion. Although there have been significant improvements in the use of conventional and biologic disease-modifying antirheumatic drugs, the systemic administration of these drugs is still limited by off-target toxicity, unstable pharmacokinetics, immunosuppression, and insufficient drug accumulation in the inflamed joints. These limitations have led to a growing interest in the local intra-articular drug delivery approaches. Polysaccharide-based nanocarriers have become an attractive platform due to their inherent biocompatibility, biodegradability, and structural similarity with the native joint extracellular matrix components. This review first introduces various polysaccharide nanocarriers that are engineered and utilized for targeted intra-articular therapy of RA. Special attention has been given to the molecular design principles that determine the size, electric charge, chemical functionalization, and stimuli-responsive properties in the inflammatory synovial microenvironment. Preclinical data from in vitro studies and animal models reveal that these systems improve joint retention, facilitate receptor-mediated cellular uptake, allow sustained drug release, inhibit pro-inflammatory cytokines, and protect cartilage while reducing systemic exposure. The review discusses the translational challenges, safety considerations, and future directions to facilitate clinical application of polysaccharide nanomedicine for precise intra-articular management of rheumatoid arthritis based on the contextual comparison to osteoarthritis and non-polysaccharide-based nanocarriers.