Extracellular vesicles (EVs) are promising drug-delivery vehicles owing to their biocompatibility and low immunogenicity. Genetic engineering of a membrane-bound EV-sorting scaffold protein empowers EVs by installing targeting moieties on the surface and enriching therapeutic cargo in the lumen. However, the choice of scaffold proteins with simple structures and short sequences is limited. Here, we conduct mass spectrometry-based proteomic studies and identify ENPP1 as a superior scaffold protein. Furthermore, we show that a truncated 144-amino acid variant, EN144, efficiently loads diverse therapeutic cargoes and outperforms conventional scaffolds. By fusing EN144 to the IL-6 decoy receptor gp130, we create engineered decoy EVs that potently inhibit inflammatory IL-6 trans-signaling. In mouse models, these EVs reduce inflammation, improve survival in sepsis, and, when targeted to cartilage, alleviate tissue damage in osteoarthritis. Our work establishes EN144 as a minimal, high-performance scaffold for EV engineering and demonstrates its broad therapeutic potential for inflammatory diseases.
© 2026. The Author(s).