Smart Hydrogel for the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease that imposes substantial physical, emotional, and socioeconomic burdens on patients. Conventional therapeutic approaches are often limited by systemic toxicity, inadequate joint targeting, and variable patient responses, highlighting the urgent need for advanced drug delivery systems. Smart hydrogels have emerged as a promising platform for RA treatment due to their unique three-dimensional hydrophilic networks, excellent biocompatibility, and tunable physicochemical properties. This review systematically summarizes the preparation strategies and design principles of smart hydrogels, with an emphasis on chemically and physically crosslinked networks as well as composite systems. It further outlines the major stimulus-responsive release mechanisms-including temperature, pH, reactive oxygen species (ROS), light, and enzyme triggers-that enable targeted and controlled drug delivery within the inflamed joint microenvironment. Among the various types discussed, temperature-responsive and multi-responsive hydrogels are most frequently investigated for their potential to achieve localized, on-demand therapy. Despite considerable preclinical progress, the clinical translation of smart hydrogels faces critical challenges, including insufficient long-term biocompatibility data, lack of standardized evaluation protocols, and difficulties in scalable manufacturing. This review aims to provide a conceptual framework for the rational design of smart hydrogels and to stimulate interdisciplinary efforts toward overcoming existing translational barriers in RA treatment.