Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by progressive synovial inflammation and joint destruction, with knee involvement prevalent in approximately 90% of patients. Current local therapies, such as intra-articular injections, often yield transient benefits owing to rapid drug clearance and failure to target pathological neovascularization, highlighting the need for innovative approaches. In this study, we developed a dual-functioning embolic microsphere platform, ETN-GMA/MS, which combines genicular artery embolization with the sustained local delivery of etanercept (ETN), a tumor necrosis factor-α inhibitor, and aimed to assess its therapeutic efficacy in suppressing synovial inflammation and aberrant angiogenesis in an in vitro rabbit model of RA. Microspheres were fabricated using gelatin methacryloyl (GelMA) via microfluidic technology and demonstrated high monodispersity, sustained drug release over 7 days in vitro, and minimal cytotoxicity or hemolysis. In an ovalbumin-induced rabbit knee RA model, ETN-GMA/MS embolization resulted in significant and long-lasting reductions in synovial thickness, serum tumor necrosis factor-α, interleukin-6, serum C-reactive protein, and erythrocyte sedimentation rate compared with those following treatment with blank microspheres and intra-articular ETN injections and in untreated controls, with hematoxylin and eosin staining confirming near-normal synovial architecture and minimal neovascularization. These findings underscore the superiority of combined embolization and sustained-release mechanisms, offering a promising minimally invasive strategy for refractory RA.