Myocardial infarction (MI)-induced impaired cardiomyocyte (CM) mitochondrial function and microenvironmental inflammatory cascades severely accelerate the progression of heart failure for compromised myocardial repair. Modulation of the crosstalk between CM mitochondrial DNA (mtDNA) and STING has been recently identified as a robust strategy in enhancing MI treatment, but remains seldom explored. To develop a novel approach that can address persistent myocardial injury using this crosstalk, we report herein construction of a biomimetic hydrogel system, Rb1/PDA-hydrogel comprised of ginsenoside Rb1/polydopamine nanoparticles (Rb1/PDA NPs)-loaded carboxylated chitosan, 4-arm-PEG-phenylboronic acid (4-arm-PEG-PBA), and 4-arm-PEG-dopamine (4-arm-PEG-DA) crosslinked networks. An optimized hydrogel formulation presents not only desired adhesion properties to the surface of the myocardium, but also adaptability for deep myocardial injection, resulting in ROS scavenging, CM mitochondrial function protection, M1 macrophage polarization inhibition through the STING pathway, and angiogenesis promotion via an internal-external spatial combination. The enhanced therapeutic efficiency is supported by the histological analysis of the infarcted area, which shows that the fibrotic area of the MI rats decreases from 58.4% to 5.5%, the thickness of the left ventricular wall increases by 1-fold, and almost complete recovery of cardiac function after 28 days of treatment. Overall, this study reported the first use of a strong adhesive and injectable hydrogel with mtDNA and STING signaling characteristics for enhanced MI treatment via an internal-external spatial combination strategy.

中文翻译：

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通过 mtDNA-STING 串扰调制仿生水凝胶介导的空间组合疗法增强心肌梗死治疗


心肌梗死（MI）诱导的心肌细胞（CM）线粒体功能受损和微环境炎症级联反应严重加速心力衰竭的进展，导致心肌修复受损。最近，调节 CM 线粒体 DNA (mtDNA) 和 STING 之间的串扰被认为是增强 MI 治疗的有效策略，但仍很少被探索。为了开发一种可以利用这种串扰解决持续性心肌损伤的新方法，我们在此报告了仿生水凝胶系统的构建，Rb1/PDA-水凝胶由负载人参皂苷Rb1/聚多巴胺纳米粒子（Rb1/PDA NPs）的羧化壳聚糖组成，4-臂-PEG-苯基硼酸（4-臂-PEG-PBA）和4-臂-PEG-多巴胺（4-臂-PEG-DA）交联网络。优化的水凝胶配方不仅具有对心肌表面所需的粘附特性，而且具有对心肌深部注射的适应性，从而实现 ROS 清除、CM 线粒体功能保护、通过 STING 途径抑制 M1 巨噬细胞极化，以及通过内部血管生成促进血管生成。 -外部空间组合。梗塞区域的组织学分析证实了治疗效率的提高，结果显示MI大鼠的纤维化面积从58.4%减少到5.5%，左心室壁厚度增加1倍，几乎完全恢复治疗 28 天后的心脏功能。总体而言，这项研究报告了首次使用具有 mtDNA 和 STING 信号特征的强粘性可注射水凝胶，通过内部-外部空间组合策略来增强 MI 治疗。