Mechanobiologically Engineered Extracellular Vesicle–Mimetic Nanocarriers for Enhanced Systemic Biodistribution and Anti-Inflammatory Therapy in Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation, abnormal vascularization, and inefficient drug accumulation in inflamed joints after systemic administration. This study aimed to develop a mechanobiologically engineered EV-mimetic nanocarrier with tunable membrane elasticity to enhance therapeutic efficacy in RA. Lipid/polymer hybrid nanocarriers were fabricated using DOTAP, DOPE, and PEO-b-PCL-b-PEO, encapsulating stem cell extract and antagomiR-155 to form tri-block copolymer artificial EVs (Tri-ARTEX). The semi-elastic Tri-ARTEX8:2 showed enhanced uptake by pro-inflammatory macrophages, promoted M1-to-M2 reprogramming in vitro, and preferential accumulation in inflamed joints in a collagen-induced arthritis mouse model, resulting in reduced inflammation and joint damage. These findings highlight membrane mechanics as a key design parameter for EV-mimetic nanocarriers targeting inflammatory diseases.