Injectable thermosensitive hydrogels for sustained intra-articular release of TNF-α inhibitors in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a progressive autoimmune disorder that is defined by synovial inflammation, progressive cartilage and bone destruction and systemic symptoms. Tumor necrosis factor-α (TNF-α) plays the central role in the pathogenesis of RA, although the systemic administration of TNF-α inhibitors is limited by rapid clearance, immunogenicity and dose-dependent adverse effect. Thus, localized intra-articular delivery of TNF-α inhibitors emerged as a promising therapeutic intervention to achieve maximal site-specific activity at minimal systemic adverse effect. Among advanced delivery systems, injectable thermosensitive hydrogels have gained specific attention due to their reversible sol-gel transitions at physiological temperatures, providing minimally invasive injectability, in vivo gel formation and sustained drug delivery in the inflammatory joint microenvironment. This work provides a comprehensive review of design principles, polymeric formulations and therapeutic potential of thermosensitive hydrogels, such as PLGA-PEG-PLGA triblock copolymers, pluronic micelles, chitosan-β-glycerophosphate and hyaluronic acid-based networks for sustained intra-articular delivery of TNF-α inhibitors. These biomaterials are highly biocompatible, biodegradable and mechanically tunable, stimulating the extracellular matrix (ECM) to support joint restoration and sustained therapeutic activity. Moreover, incorporation of pH-, redox-, and enzyme-responsive functionalities provides adaptive release in response to inflammatory cytokines and maximizing therapeutic selectivity. Therefore, the thermosensitive hydrogels provide a next-generation delivery platform for site-specific treatment of RA by mobilizing biomaterial innovation, immunological selectivity, enhancing intra-articular residence time, reducing systemic exposure and maintaining physiological TNF-mediated immune functions, this system offer a transformative future for the development of safer, more stable and patient-specific management of RA.