Recent Advances in Stimuli Responsive In-Situ Gelling System for the Management of Rheumatoid Arthritis

The chronic autoimmune inflammatory disease known as rheumatoid arthritis (RA) is marked by irreparable joint damage, increasing cartilage loss, immune cell infiltration, and persistent synovial inflammation. Approximately 0.24% of people worldwide suffer from RA, with a higher frequency among women than men. Even though there are many different therapeutic options available today, such as biologic agents, synthetic drugs, and conventional disease-modifying anti-rheumatic drugs (DMARDs), their clinical efficacy is frequently constrained by frequent dosing requirements, short biological half-lives, non-specific drug distribution, and systemic adverse effects. As a result, maintaining treatment efficacy while reducing toxicity continues to be a significant management problem for RA. Stimuli-responsive in situ gelling systems have been recently developed as promising localized drug delivery methods for the treatment of RA. These smart systems have sol-gel transition in response to physiological stimuli, including temperature, pH, ionic concentration, enzymes, or inflammatory mediators present in the diseased joint environment. This responsiveness allows for prolonged retention at the target site, controlled drug release, increased therapeutic efficacy, and reduced systemic exposure. This review summarizes the recent progress in stimuli-responsive in-situ gelling systems for RA therapy, with an emphasis on design principles, gelation mechanisms, formulation strategies, evaluation methods, and therapeutic applications. Special emphasis is placed on thermosensitive, pH-responsive, and ion-sensitive hydrogels and their advantages, limitations, and translational potential. Overall, these intelligent in-situ gelling platforms offer significant opportunities for improving targeted drug delivery, patient compliance, and long-term treatment outcomes in rheumatoid arthritis.