Scholarlink

<p>Myocardial infarction triggers pathological remodeling that often progresses to irreversible fibrosis and heart failure, representing a major unmet therapeutic need. The infarcted heart exhibits persistently elevated levels of reactive oxygen species (ROS), thereby actively driving fibrotic signaling and creating a highly oxidative microenvironment. The development of efficient and safe small interfering RNA (siRNA) delivery vectors remains a critical challenge for clinical gene therapy applications. In this study, we designed and synthesized a series of ROS-responsive hyperbranched polycations, denoted as KPBPs, via a ring-opening reaction between proline-rich peptides and pentaerythritol tetraglycidyl ether. The resulting KPBP carrier, especially KPBP-2, which had a higher proline content, exhibited high siRNA binding affinity, oxidative micro-environment-responsive degradation, and subsequent controlled siRNA release. <i>In vitro</i>, KPBP/siRNA complexes demonstrated superior biocompatibility, enhanced cellular uptake, and improved lysosomal escape compared to conventional polyethylenimine (PEI) transfection agents. Notably, potent silencing of the transforming growth factor beta 1 (<i>Tgfb1</i>) gene was achieved with the KPBP-2/siR-Tgfb1 complex across multiple cell lines, exceeding the performance of PEI at optimal formulation ratios. In a myocardial infarction mouse model, systemic administration of KPBP-2/siR-Tgfb1 significantly attenuated cardiac fibrosis, preserved ventricular structure, and restored heart function, as validated by echocardiographic and histological analyses. Comprehensive biosafety assessment revealed minimal cytotoxicity and exceptional hemocompatibility. These findings establish KPBP as a highly promising and translatable siRNA delivery platform for the treatment of fibrotic and other ROS-related diseases.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Reactive oxygen species-responsive small interfering RNA nanotherapeutics for treatment of myocardial fibrosis

  • 期刊论文

  • 发表日期：

    2025年11月25日

查看全文
  • Wei-Jie Yang,
  • Xiangxiang Luo,
  • Mansheng Chen,
  • Yang Li,
  • Yulin Li,
  • Chen Xu,
  • Yihui Shao,
  • Fu-Jian Xu

摘要

Myocardial infarction triggers pathological remodeling that often progresses to irreversible fibrosis and heart failure, representing a major unmet therapeutic need. The infarcted heart exhibits persistently elevated levels of reactive oxygen species (ROS), thereby actively driving fibrotic signaling and creating a highly oxidative microenvironment. The development of efficient and safe small interfering RNA (siRNA) delivery vectors remains a critical challenge for clinical gene therapy applications. In this study, we designed and synthesized a series of ROS-responsive hyperbranched polycations, denoted as KPBPs, via a ring-opening reaction between proline-rich peptides and pentaerythritol tetraglycidyl ether. The resulting KPBP carrier, especially KPBP-2, which had a higher proline content, exhibited high siRNA binding affinity, oxidative micro-environment-responsive degradation, and subsequent controlled siRNA release. In vitro, KPBP/siRNA complexes demonstrated superior biocompatibility, enhanced cellular uptake, and improved lysosomal escape compared to conventional polyethylenimine (PEI) transfection agents. Notably, potent silencing of the transforming growth factor beta 1 (Tgfb1) gene was achieved with the KPBP-2/siR-Tgfb1 complex across multiple cell lines, exceeding the performance of PEI at optimal formulation ratios. In a myocardial infarction mouse model, systemic administration of KPBP-2/siR-Tgfb1 significantly attenuated cardiac fibrosis, preserved ventricular structure, and restored heart function, as validated by echocardiographic and histological analyses. Comprehensive biosafety assessment revealed minimal cytotoxicity and exceptional hemocompatibility. These findings establish KPBP as a highly promising and translatable siRNA delivery platform for the treatment of fibrotic and other ROS-related diseases.