Abstract
Rheumatoid arthritis (RA) involves chronic inflammation, oxidative stress, and complex immune cell interactions, leading to joint destruction. Traditional treatments are often limited by off-target effects and systemic toxicity. This study introduces a novel therapeutic approach using hyaluronic acid (HA)-conjugated, redox-responsive polyamino acid nanogels (HA-NG) to deliver tacrolimus (TAC) specifically to inflamed joints. The nanogels' disulfide bonds enable controlled TAC release in response to high intracellular glutathione (GSH) levels in activated macrophages, prevalent in RA-affected tissues. In vitro results demonstrated that HA-NG/TAC significantly reduced TAC toxicity to normal macrophages and showed high biocompatibility. In vivo, HA-NG/TAC accumulated more in inflamed joints compared to non-targeted NG/TAC, enhancing therapeutic efficacy and minimizing side effects. Therapeutic evaluation in collagen-induced arthritis (CIA) mice revealed HA-NG/TAC substantially reduced paw swelling, arthritis scores, synovial inflammation, and bone erosion while suppressing pro-inflammatory cytokine levels. These findings suggest that HA-NG/TAC represents a promising targeted drug delivery system for RA, offering potential for more effective and safer clinical applications.