Engineering Tripterygium wilfordii-derived exosome-like nanoparticles for targeted therapy in rheumatoid arthritis

Aim: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by excessive activation of pro-inflammatory macrophages and elevated levels of reactive oxygen species (ROS), resulting in synovial hyperplasia, cartilage destruction, and joint dysfunction. This study aimed to develop an engineered Tripterygium wilfordii-derived exosome-like nanoparticle system (TWELP@GlcN-HA) that integrates antioxidant, anti-inflammatory, immunomodulatory, and joint-targeting activities for synergistic RA therapy. Methods: Tripterygium wilfordii-derived exosome-like nanoparticles (TWELP) were isolated from fresh Tripterygium wilfordii and sequentially surface-modified with glucosamine (GlcN) for cartilage protection and hyaluronic acid (HA) for targeted uptake by inflammatory cells. Their physicochemical properties, including morphology, particle size, structural integrity, and surface potential, were systematically characterized. In vitro assays were performed to evaluate ROS scavenging, inhibition of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)], and macrophage polarization. Biodistribution and therapeutic efficacy were evaluated in a collagen-induced arthritis (CIA) mouse model by assessing synovial inflammation, cartilage damage, joint morphology, and joint function. Results: TWELP@GlcN-HA exhibited a uniform spherical morphology, stable surface potential, and preserved structural integrity. In vitro, it efficiently scavenged ROS, suppressed TNF-α and IL-6 secretion, and promoted macrophage polarization from M1 to M2, thereby restoring immune homeostasis. In vivo, HA-mediated targeting promoted nanoparticle accumulation in inflamed joints. TWELP@GlcN-HA significantly alleviated synovial inflammation and cartilage destruction, improved joint morphology and function, and exhibited excellent biosafety with no systemic toxicity. Conclusion: TWELP@GlcN-HA provides a multifunctional combinatorial strategy for RA treatment by synergistically regulating ROS, reprogramming pro-inflammatory macrophages, protecting cartilage, and achieving targeted joint delivery. Its enhanced therapeutic efficacy and favorable safety profile make it a promising candidate for future clinical translation in RA management.