ROS- and iron ion-responsive gelatin modulates the pathological microenvironment to enhance myocardial infarction treatment.

Myocardial infarction (MI) generates a pathological microenvironment characterized by ischemia and hypoxia, and this increases mortality and morbidity worldwide. We fabricated p-hydroxyphenylpropionic acid-modified gelatin (GTN), a dual-responsive system capable of in situ gelation in the presence of hydrogen peroxide (H2O2) or iron ions. This feature enables GTN to cross-link in the infarcted myocardium, where excessive reactive oxygen species (ROS) and iron ions trigger ferroptosis. The successful modification of gelatin was verified, along with its time- and concentration-dependent responsiveness to H2O2 and iron ions in vitro. We further assessed the biocompatibility, ROS-scavenging activity, and cytoprotective effects of GTN in hostile MI microenvironments. Death receptor 5 fusion protein (DR5) was incorporated into the hydrogel to construct DR5@GTN, aiming to alleviate cardiomyocyte apoptosis. In vivo experiments demonstrated that GTN effectively targeted and accumulated in the infarcted region via transglutaminase-mediated recognition, thereby remodeling the pathological microenvironment. DR5@GTN significantly restored cardiac functions, increased the left ventricular ejection fraction, and reduced the infarct size. DR5@GTN attenuated myocardial fibrosis, promoted angiogenesis, suppressed cardiomyocyte apoptosis, decreased ROS levels, and inhibited myocardial hypertrophy. Collectively, DR5@GTN regulated the "ROS-iron-apoptosis" axis with favorable in situ gelation properties, and this represents a promising strategy for myocardial repair by ameliorating the harsh microenvironment following MI. STATEMENT OF SIGNIFICANCE.