Self-homing TGF-β1 traps: Engineered vasorin vesicles as smart biomaterials for targeted anti-fibrotic therapy after myocardial infarction

Cardiac fibrosis is a critical pathological process following myocardial infarction (MI), predominantly mediated by transforming growth factor-β1 (TGF-β1), for which effective targeted therapies remain limited. Vasorin is a cell membrane glycoprotein that functions as an endogenous antagonist of TGF-β1. To enhance its binding efficiency, we engineered vasorin variants incorporating site-specific fluorosulfate-L-tyrosine (FSY) through genetic code expansion. This chemical modification enables sulfur-fluoride exchange (SuFEx) reactions and covalent trapping of TGF-β1, thereby improving target selectivity. For lesion-specific delivery, hybrid membrane vesicles (HM-MVP) were constructed by fusing FSY-modified, vasorin-anchored HEK293T cell membranes with thrombus-homing platelet (PLT) membranes. In murine MI models, HM-MVP selectively accumulated within infarcted myocardial tissue and exhibited superior TGF-β1 binding affinity, resulting in more pronounced anti-fibrotic effects compared to native vasorin vesicles. This targeted therapeutic approach was associated with significantly improved cardiac structural preservation and functional recovery post-MI, highlighting favorable drug-like characteristics. Collectively, these findings reveal, for the first time, the cardioprotective and anti-fibrotic potential of vasorin, and elucidate a novel therapeutic paradigm by synergizing FSY-engineered vasorin with biomimetic vesicle delivery to address maladaptive TGF-β1 signaling in cardiac fibrosis. • Vasorin is firstly demonstrated to protect against cardiac fibrosis post-infarction. • Engineering vasorin with FSY strengthens TGF-β1 binding and inhibition. • Hybrid membrane vesicles bearing vasorin-FSY achieve targeted and potent anti-fibrotic effects in infarcted myocardium.