Mannose-targeted iguratimod liposomes in an HA-derived hydrogel: a synergistic therapy for rheumatoid arthritis via macrophage targeting and ROS scavenging.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and irreversible joint damage. Iguratimod (IGU), a novel small-molecule disease-modifying antirheumatic drug (DMARD), is limited by low solubility, inadequate joint accumulation and hepatotoxicity when administered orally. To address these limitations, we developed an injectable composite hydrogel (IGU-Man-Lip@Vc-HA) by incorporating mannose-modified IGU liposomes (IGU-Man-Lip) into a vitamin C-functionalized hyaluronic acid (Vc-HA) matrix with ROS-scavenging activity. In this system, IGU-Man-Lip overcame the poor solubility of iguratimod and actively targeted synovial macrophages via overexpressed mannose receptors (MR), thereby downregulating inflammatory cytokine levels and exerting bone-protective effects. Concurrently, the Vc-HA hydrogel scavenged ROS to remodel the inflammatory microenvironment. Furthermore, the resistance of Vc-HA to degradation significantly prolonged intra-articular retention, thereby enhancing drug accumulation in joints. This hybrid delivery system exhibited favorable biocompatibility, as well as potent anti-inflammatory and bone-protective efficacy. In collagen-induced arthritis (CIA) rats, intra-articular injections achieved significant joint enrichment, potent anti-inflammatory activity and articular repair without detectable systemic toxicity. This multifunctional composite system constitutes a synergistic RA therapeutic strategy by concurrently addressing targeted drug delivery and oxidative stress to improve anti-inflammatory efficacy along with bone protective effects, providing a promising RA-specific treatment approach.