Extracellular Matrix‐Coated Vesicles as a Biomimetic Model of MembraneMatrix Interplay

Abstract Artificial membrane systems have enabled powerful studies of lipid dynamics and bilayer mechanics, yet they lack the structural complexity of living cells, where membranes are embedded within an extracellular matrix (ECM). Here, a biomimetic platform is presented that integrates fibronectin (FN) and collagen type I (COL) onto the surface of giant unilamellar vesicles (GUVs) to investigate ECM‐induced modulation of membrane properties. ECM coating imparts distinct, protein‐specific effects on vesicle curvature, mechanical resilience, and lipid diffusivity. FN promotes vesicle budding and membrane softening, while COL induces rugged membrane topographies and mechanical stiffening. Furthermore, ECM proteins reshape the geometry and stability of phase‐separated lipid domains, mimicking curvature heterogeneity observed in cell membranes. Strikingly, vesicle budding events observed in FN‐coated GUVs resemble exosome‐like release, suggesting that ECM identity not only dictates membrane mechanics but may also regulate vesicle biogenesis. This system captures essential mechanobiological interactions between the ECM and the plasma membrane in the absence of transmembrane linkers. The findings provide a tunable platform for studying ECM–membrane coupling and ECM‐vesicle interplay with relevance to exosome modeling, offering new directions for engineering responsive synthetic cells and advancing extracellular vesicle biology.