Purpose <p>This study aims to revolutionize rheumatoid arthritis (RA) treatment by developing an optimized silver nanoparticle (AgNP)-loaded nanogel for targeted transdermal delivery. RA is a chronic autoimmune disorder requiring innovative therapies to address the limitations of existing treatments, including systemic side effects and incomplete symptom control. The research focuses on engineering a nanogel formulation to achieve sustained drug release and enhanced therapeutic efficacy.</p> Methods <p>The nanogel was designed using a central composite design to optimize key physicochemical properties, including viscosity, spreadability, and pH, ensuring ease of application, skin compatibility, and maximal coverage. The incorporation of <i>Lantana montevidensis</i> aqueous extract further enhances the formulation’s therapeutic potential. This plant extract is known for its anti-inflammatory properties, providing a synergistic effect with the AgNPs. The therapeutic potential of the nanogel was assessed through in vitro proteinase inhibition, in vivo anti-inflammatory and anti-arthritic studies.</p> Results <p>The nanogel demonstrated superior anti-inflammatory and anti-arthritic efficacy compared to conventional treatments. Sustained drug release was evaluated in vitro, achieving a controlled release profile of 95.36% over 8&#xa0;h. It significantly reduced edema, preserved joint structure, and inhibited proteinase activity, preventing cartilage degradation. The sustained release profile minimized dosing frequency and potential side effects, ensuring consistent therapeutic levels at the target site.</p> Conclusion <p>The optimized AgNP-loaded nanogel represents a breakthrough in RA treatment, offering a biocompatible and stable formulation with enhanced therapeutic outcomes. Its controlled drug delivery and synergistic anti-inflammatory effects provide a promising approach for improving RA management and patient quality of life.</p> Graphical Abstract <p></p>