siRNA-mediated RNA interference (RNAi) against inflammation-related genes provides a promising modality for the treatment of myocardial ischemia reperfusion (IR) injury, and its success is critically dependent on the development of efficient yet safe siRNA delivery vehicles. Herein, we developed a bioreducible, branched poly(β-amino ester) with built-in redox-responsive domains (BPAE-SS) for the effective ICAM-1 siRNA delivery into injured rat cardiac microvascular endothelial cells (RCMECs). The branched BPAE-SS with a multivalent structure afforded potent siRNA binding affinity compared to its linear analogue, while upon internalization into RCMECs it was instantaneously degraded by intracellular glutathione (GSH) into small segments to mediate “on-demand” siRNA release and diminish the toxicity of post-transfection materials. By synchronizingly overcoming these critical barriers, BPAE-SS mediated remarkable ICAM-1 knockdown in IR-injured rats at 400 μg siRNA per kg via single i.v. injection, and subsequently suppressed myocardial inflammation, apoptosis, and fibrosis to recover the cardiac function. This study therefore provides a unique delivery system that can address the multiple critical challenges against non-viral siRNA delivery, and the potent therapeutic efficacy of BPAE-SS-mediated ICAM-1 silencing provides a promising strategy for the anti-inflammatory treatment of myocardial IR injury.

中文翻译：

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可生物还原的支链聚（β-氨基酯）介导抗炎 ICAM-1 siRNA 递送以对抗心肌缺血再灌注 (IR) 损伤。

针对炎症相关基因的 siRNA 介导的 RNA 干扰 (RNAi) 为治疗心肌缺血再灌注 (IR) 损伤提供了一种有前途的方式，其成功关键取决于开发高效而安全的 siRNA 递送载体。在此，我们开发了一种具有内置氧化还原响应结构域 (BPAE-SS) 的可生物还原的支链聚 (β-氨基酯)，用于有效地将 ICAM-1 siRNA 递送到受伤的大鼠心脏微血管内皮细胞 (RCMECs) 中。与线性类似物相比，具有多价结构的分支 BPAE-SS 提供了有效的 siRNA 结合亲和力，而在内化到 RCMECs 后，它会被细胞内谷胱甘肽 (GSH) 瞬间降解成小片段，以介导“按需”释放 siRNA 并减少转染后材料的毒性。通过单次静脉注射，随后抑制心肌炎症、细胞凋亡和纤维化以恢复心脏功能。因此，本研究提供了一种独特的递送系统，可以解决针对非病毒 siRNA 递送的多重关键挑战，并且 BPAE-SS 介导的 ICAM-1 沉默的有效治疗效果为心肌 IR 的抗炎治疗提供了有希望的策略受伤。