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Myocardial ischemia-reperfusion (MIR) injury drives adverse remodeling and heart failure after ST-elevation myocardial infarction (STEMI), yet no therapy directly targets the fibrotic response. Here, we developed a good manufacturing practice-compatible extracellular vesicle (EV)-enriched secretome from bone marrow mesenchymal stromal cells and identified a laminin-521-based production strategy suitable for clinical translation. The EV-enriched secretome exhibited in vitro immunomodulatory activity, and in murine MIR-injury models, treatment preserved left ventricular ejection fraction, reduced platelet-derived growth factor receptor beta (PDGFR beta)-associated myofibroblast activation quantified by positron emission tomography (PET) imaging, attenuated fibrosis, and promoted reparative macrophage polarization. In a clinically relevant porcine ischemia-reperfus ion model, intracoronary administration was cardioprotective. We further developed a clinically approved PDGFR beta-targeted PET-imaging platform for longitudinal assessment of fibrotic activity in STEMI patients, where preliminary observations suggest that myofibroblast activation persists for up to 2 months after STEMI in selected patients. Together, these findings establish a translational therapeutic-diagnostic framework for individualized management of MIR injury.