Intrapericardially injected hydrogel loaded with stromal cell secretome microparticles improves post-infarction myocardial repair in pigs

BACKGROUND AND AIMS: Myocardial infarction (MI) stands as a prominent manifestation of cardiovascular events. Most of the regenerative effects of stem cell therapies for MI are paracrine. A clinically translatable strategy that harnesses regenerative secretome while enabling minimally invasive delivery is needed. This study evaluated Regenerative Encapsulated Secretome as Cardiac Acellular Therapy (RESCAT), a formulation composed of cardiac stromal cell-derived secretome encapsulated in microparticles and embedded within a hyaluronic acid hydrogel, delivered via intrapericardial injection in a porcine model of MI. METHODS: MI was induced using minimally invasive techniques. RESCAT was administered through clinically feasible intrapericardial delivery. Cardiac structure and function were assessed longitudinally in vivo. After the endpoint, infarct size and cardiomyocyte cell-cycle activity were assessed with histology. Single-nucleus RNA sequencing was performed to characterize cardiomyocyte transcriptional states and identify molecular pathways associated with therapeutic response. RESULTS: RESCAT-treated pigs showed improved cardiac function and reduced infarct size compared with control groups. Enhanced cardiomyocyte cell-cycle activity and alterations in cardiomyocyte functional state were also observed. Single-nucleus transcriptomic analysis identified an FN1-expressing cardiomyocyte subtype linked to the activation of the PI3K-Akt pathway, which plays a role in cell survival and growth. CONCLUSIONS: Intrapericardial delivery of RESCAT promotes functional and structural cardiac recovery in a clinically relevant porcine MI model. These findings support a minimally invasive, off-the-shelf acellular therapeutic strategy that enhances endogenous repair mechanisms and provides a foundation for translational development in ischaemic heart disease.