Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune condition that leads to chronic arthritis, disability, and reduced lifespan. Current therapies show limited effectiveness and often cause severe side effects, with up to 50% of patients discontinuing disease-modifying antirheumatic drugs (DMARDs) due to unsatisfactory outcomes. Natural bioactive compounds (NBCs), such as glycosides, alkaloids, terpenoids, flavonoids, polyphenols, and coumarins, have gained attention for their immunomodulatory and anti-inflammatory properties. However, challenges like poor solubility, high dosage requirements, short action duration, and low tissue specificity hinder their clinical use. Nanoparticle (NP)-based delivery systems, including lipid NPs (LNPs), polymer carriers, and inorganic nanocarriers, have been designed to address these challenges through passive, active, and stimuli-responsive strategies. NBC-loaded NPs target immune dysfunction, synovial hyperplasia, bone destruction, angiogenesis, inflammation, and oxidative stress (OS) in RA. This article highlights recent advancements in NBCs for RA treatment, nanoformulation design, and targeted mechanisms, while addressing challenges and future directions in this field. The integration of cutting-edge nanotechnology has demonstrated significant potential to overcome traditional barriers such as low bioavailability and off-target effects through intelligent NPs design. Future research should enhance artificial intelligence (AI)-driven modeling to predict drug-nanocarrier interactions, develop biomarker frameworks for precision nanomedicine, and optimize RA management.