Phenylated Lipid Nanoparticles Specifically Targeting the Ankle Joint for Delivery of miR-709-z in the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes joint swelling and pain, often leading to disability. Despite advances in nonsteroidal anti-inflammatory drugs and anticytokine biologics, their use remains limited due to the complexity of cytokine interactions, long-term drug dependence, and side effects. Recent studies emphasize the crucial role of miRNA in regulating inflammation, but their degradation and poor druggability hinder clinical application. This study identified that miRNA-709-z, derived from anti-inflammatory exosomes, exhibited strong anti-inflammatory effects. To overcome delivery challenges, an ionizable lipidoid incorporating a benzene ring, MO12, was synthesized and employed to formulate lipid nanoparticles (LNPs) for targeted delivery of miRNA-709-z to the ankle joint. MO12-LNPs not only significantly improved the cellular uptake and stability of miRNA-709-z but also enhanced its accumulation in the inflamed ankle joints of collagen-induced arthritis (CIA) mice. Treatment with MO12-LNP@miRNA-709-z effectively alleviated ankle inflammation in this model. Further studies revealed that MO12-LNP@miRNA-709-z reduced proinflammatory cytokines, inhibited synovial inflammation, and protected cartilage, preventing joint damage. This study not only developed an efficient miRNA delivery system but also demonstrated the potential of miRNA-based cytokine silencing in clinical RA treatment.