Bioadhesive Scaffold for Dual Delivery of Methotrexate‐Loaded Liposomes and Chondrogenic miRNA in Advanced Rheumatoid Arthritis Therapy

ABSTRACT Rheumatoid arthritis (RA) progressively develops from inflammatory synovitis to irreversible osteochondral destruction, with current clinical interventions offering only transient immunosuppression and lacking regenerative potential. Herein, we develop a bioadhesive scaffold integrating inflammation‐responsive methotrexate (MTX) nanoparticles and chondrogenic miRNA‐140 delivery systems for synergistic immunomodulation and osteochondral regeneration in advanced RA. The adhesive scaffold matrix consists of collagen and polydopamine‐modified‐hyaluronic acid (PDA/HA), crosslinked with polyethylene glycol diglycidyl ether (PEGDE), which provides robust mesenchymal stem cell adhesion and prolongs nanomedicine retention while establishing a regenerative microenvironment. The engineered system features MMP‐labile polydopamine‐doped lipid nanoparticles (PLNP) that rapidly release MTX in inflammatory conditions to suppress synovitis, working in concert with reactive oxygen species‐scavenging gallic acid‐modified chitosan nanoparticles (GC) that protect and effectively deliver miRNA‐140 to restore chondrogenesis. In collagen‐induced advanced arthritis models, this dual‐stage therapy demonstrated sequential therapeutic action by initial immunomodulation followed by structural regeneration, yielding complete osteochondral restoration characterized by hyaline cartilage formation with physiological matrix features and integrated subchondral bone restoration. This work represents a significant progress in advanced RA treatment by transitioning from symptomatic management to true disease modification, combining precise immunomodulation with functional tissue regeneration through intelligent biomaterial design.