A bioactive heart-derived ECM hydrogel potentiates Astragaloside IV-mediated microvascular regeneration.

Impaired microcirculation and insufficient angiogenesis critically limit functional recovery after myocardial infarction (MI), yet effective strategies for localized and sustained vascular regeneration remain lacking. Here, we develop a heart-specific extracellular matrix-based hydrogel for the intrapericardial delivery of Astragaloside IV (AS-IV), a pro-angiogenic bioactive monomer derived from traditional Chinese medicine. The bioactive hydrogel is fabricated from decellularized porcine heart extracellular matrix (HdECM), which provides a biomimetic cardiac microenvironment while enabling sustained local release of AS-IV. Distinct from conventional intramyocardial injection, intrapericardial administration allows the hydrogel to form a patch-like depot on the cardiac surface, achieving prolonged cardiac retention with minimal tissue injury. Under oxygen-glucose deprivation, the AS-IV@HdECM hydrogel synergistically enhances endothelial cell survival, migration, and angiogenic capacity while suppressing apoptosis. In a rat MI model, localized delivery of AS-IV via HdECM markedly promotes neovascularization, attenuates myocardial fibrosis, reduces cardiomyocyte apoptosis, and significantly improves cardiac function. Mechanistically, integrative proteomic and network pharmacology analyses, together with experimental validation, indicate that the therapeutic effects are associated with activation of the EGFR/Raf-MEK-ERK signaling pathway. This work establishes a localized therapeutic paradigm that integrates heart-specific matrix cues with traditional Chinese medicine, offering a translational biomaterials strategy for microvascular regeneration and cardiac repair after MI.