ROS- and Iron Ion-Responsive Gelatin Modulates the Pathological Microenvironment to Enhance Myocardial Infarction Treatment.
basic_science · Level V
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- Record sourced from PubMed, PMID 42612941.
- Also identified by DOI 10.1016/j.actbio.2026.08.030.
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Abstract
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 (H<sub>2</sub>O<sub>2</sub>) 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 H<sub>2</sub>O<sub>2</sub> 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: ● Adaptively responds to and eliminates ROS and iron ions at the infarcted region, matching the pathological characteristics of the MI microenvironment. ● Fosters angiogenesis in the infarcted region, mediates extracellular matrix remodeling, and synergistically attenuates cardiomyocyte death. ● Represents the first attempt to validate the feasibility of in situ gelation therapy for myocardial infarction via a minimally invasive strategy.