Mechanobiologically Engineered Mimicry of Extracellular Vesicles for Improved Systemic Biodistribution and Anti‐Inflammatory Treatment Efficacy in Rheumatoid Arthritis

Liposomal membrane elasticity is a controlling parameter in designing liposome-based drug delivery systems and significantly affects biodistribution and biofunctional effects. Although extensively investigated in tumor models, the impact of liposomal membrane elasticity on rheumatoid arthritis (RA) remains underexplored. RA presents unique challenges, such as tortuous blood vessels, increased permeability, and chronic inflammation, which necessitate a specialized drug delivery strategy. This study aims to address these challenges by developing an engineered mimicry of extracellular vesicles (EVs) that is based on a lipid/polymer hybrid system incorporating poly(ethylene oxide)-b-poly(ε-caprolactone)-b-poly(ethylene oxide) (PEO-b-PCL-b-PEO) to improve mechanical robustness and therapeutic performance.Tri-ARTEX is developed as a lipid/polymer hybrid liposome encapsulating stem cell extract (CE) and microRNA (AntagomiR155), and tuned its membrane elasticity by varying the PEO-b-PCL-b-PEO fraction. Tri-ARTEX exhibited enhanced cellular uptake in Raw 264.7 macrophages as the PEO-b-PCL-b-PEO fraction increases. However, semi-elastic Tri-ARTEX_8:2 showed distinct biodistribution profiles and therapeutic effects in a murine collagen-induced arthritis (CIA) model. Compared to its soft and rigid counterparts, semi-elastic Tri-ARTEX_8:2 improved blood circulation, targeted accumulation in inflamed joints, and anti-inflammatory efficacy. Our findings suggest that these mechanobiologically engineered liposomal EV mimics with regulated membrane elasticity provide new capabilities for designing drug nanocarriers for targeted RA therapy and help to address the unique pathophysiological challenges of RA.