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

IF 10.4 1区医学 Q1 ENGINEERING, BIOMEDICAL

Acta Biomaterialia Pub Date : 2026-10-01 Epub Date: 2026-08-18 DOI:10.1016/j.actbio.2026.08.030

Xiaoyu Liang, Xuanling Li, Xue Fu, Kaijing Liu, Changduo Wang, Ni Zhu, Chao Liu, Chunxiao Qi, Jing Yang

{"title":"ROS- and iron ion-responsive gelatin modulates the pathological microenvironment to enhance myocardial infarction treatment","authors":"Xiaoyu Liang, Xuanling Li, Xue Fu, Kaijing Liu, Changduo Wang, Ni Zhu, Chao Liu, Chunxiao Qi, Jing Yang","doi":"10.1016/j.actbio.2026.08.030","DOIUrl":null,"url":null,"abstract":"<div><div>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.</div></div><div><h3>Statement of significance</h3><div><ul><li><span>•</span><span><div>Adaptively responds to and eliminates ROS and iron ions at the infarcted region, matching the pathological characteristics of the MI microenvironment.</div></span></li><li><span>•</span><span><div>Fosters angiogenesis in the infarcted region, mediates extracellular matrix remodeling, and synergistically attenuates cardiomyocyte death.</div></span></li><li><span>•</span><span><div>Represents the first attempt to validate the feasibility of in situ gelation therapy for myocardial infarction via a minimally invasive strategy.</div></span></li></ul></div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"223 ","pages":"Pages 259-276"},"PeriodicalIF":10.4000,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Biomaterialia","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1742706126005623","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/8/18 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}

引用次数: 0

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 (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

•
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.

查看原文本刊更多论文

ROS-和铁离子反应性明胶调节病理微环境以增强心肌梗死治疗。

心肌梗死（MI）产生了一个以缺血和缺氧为特征的病理微环境，这增加了全世界的死亡率和发病率。我们制备了对羟基苯基丙酸修饰明胶（GTN），这是一种双响应系统，能够在过氧化氢（H2O2）或铁离子存在下原位凝胶化。这一特征使GTN在梗死心肌中交联，过量的活性氧（ROS）和铁离子触发铁下垂。验证了明胶的成功改性，以及其对H2O2和铁离子的体外反应时间和浓度依赖性。我们进一步评估了GTN在不良MI微环境中的生物相容性、ros清除活性和细胞保护作用。将死亡受体5融合蛋白（Death receptor 5 fusion protein, DR5）掺入水凝胶构建DR5@GTN，旨在缓解心肌细胞凋亡。体内实验表明，GTN通过转谷氨酰胺酶介导的识别有效靶向并积聚在梗死区域，从而重塑病理微环境。DR5@GTN显著恢复心功能，增加左心室射血分数，减小梗死面积。DR5@GTN减轻心肌纤维化，促进血管生成，抑制心肌细胞凋亡，降低ROS水平，抑制心肌肥大。总的来说，DR5@GTN调节“ROS-铁凋亡”轴具有良好的原位凝胶特性，这代表了一种有希望的心肌修复策略，通过改善心肌梗死后恶劣的微环境。意义说明：●适应性地响应并消除梗死区域的ROS和铁离子，符合心肌梗死微环境的病理特征。促进梗死区血管生成，介导细胞外基质重塑，并协同减轻心肌细胞死亡。●首次尝试通过微创策略验证原位凝胶治疗心肌梗死的可行性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Acta Biomaterialia 工程技术-材料科学：生物材料

CiteScore

16.80

自引率

3.10%

发文量

776

审稿时长

30 days

期刊介绍： Acta Biomaterialia is a monthly peer-reviewed scientific journal published by Elsevier. The journal was established in January 2005. The editor-in-chief is W.R. Wagner (University of Pittsburgh). The journal covers research in biomaterials science, including the interrelationship of biomaterial structure and function from macroscale to nanoscale. Topical coverage includes biomedical and biocompatible materials.