Intelligently Actuating Dual-Barrier Hyaluronic Acid-Functionalized Inflammation-Responsive Nanohydrogel for Targeted Rheumatoid Arthritis Therapy

Rheumatoid arthritis (RA) is a chronic autoimmune condition marked by persistent synovial inflammation, cartilage degradation, and progressive joint dysfunction. Current intra-articular glucocorticoid therapies, though effective, are limited by rapid drug clearance, systemic side effects, and the need for repeated dosing. To overcome these limitations, we developed an inflammation-responsive, dual-barrier nanohydrogel system (Dex-LNP-HG) for sustained and targeted intra-articular delivery of dexamethasone (Dex). This platform integrates hyaluronic acid (HA)-functionalized Dex-loaded lipid nanoparticles (Dex-LNPs) within a matrix metalloproteinase (MMP)-sensitive hydrogel, enabling enzyme-triggered degradation and subsequent CD44 receptor-mediated uptake by activated macrophages at inflamed joint sites. Upon exposure to elevated MMP levels, the hydrogel degrades, enabling the release of Dex-LNPs, which are subsequently taken up by activated macrophages via CD44 receptor-mediated endocytosis. This dual-triggered delivery system ensures site-specific, controlled release of Dex, minimizing systemic exposure and enhancing therapeutic precision. In preclinical RA models, a single intra-articular injection of Dex-LNP-HG led to a 6.5-fold reduction in synovial inflammation and a 7-fold reduction in joint damage, confirming both efficacy and prolonged retention. The system successfully avoids initial burst release, reduces the injection frequency, and improves drug localization at the disease site. By integrating HA's biocompatibility and targeting potential with enzyme-responsive release kinetics, Dex-LNP-HG represents a significant advancement in nanotherapeutic strategies for RA. This approach addresses key limitations of conventional therapies, offering improved efficacy, safety, and patient compliance.