腹主动脉瘤(AAA)是一种危及生命的血管疾病,而目前缺乏阻止AAA进展的药物干预措施。为了解决AAA的多方面病理问题,这项工作开发了一种新型的多功能基因递送系统,以同时递送靶向MMP-2和MMP-9的两种siRNA。系统(TPNs-siRNA),通过表没食子儿茶素没食子酸酯(EGCG)的氧化聚合和自组装形成,在自组装过程中有效地封装siRNA。TPNs-siRNA保护siRNA免受生物降解,促进细胞内siRNA转染,促进溶酶体逃逸,并释放siRNA以沉默MMP-2和MMP-9。此外,TPNs,作为一种多种生物活性材料,减轻氧化应激和炎症,促进巨噬细胞的M1-M2复极化,抑制细胞钙化和凋亡。在AAA小鼠的实验中,TPNs-siRNA在静脉内递送后在动脉瘤组织中积累并持续存在,证明TPNs-siRNA可以显著分布在与AAA发病机制相关的巨噬细胞和VSMC中。利用载体固有的多生物活性特性,通过TPN的靶向siRNA递送对于增强的AAA治疗具有协同作用.此外,TPNs-siRNA逐渐代谢并从体内排出,导致优异的生物相容性。因此,TPNs作为一种有前途的多生物活性纳米疗法和用于有效AAA疗法的靶向递送纳米载体出现。
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, while there is a lack of pharmaceutical interventions to halt AAA progression presently. To address the multifaceted pathology of AAA, this work develops a novel multifunctional gene delivery system to simultaneously deliver two siRNAs targeting MMP-2 and MMP-9. The system (TPNs-siRNA), formed through the oxidative polymerization and self-assembly of epigallocatechin gallate (EGCG), efficiently encapsulates siRNAs during self-assembly. TPNs-siRNA safeguards siRNAs from biological degradation, facilitates intracellular siRNA transfection, promotes lysosomal escape, and releases siRNAs to silence MMP-2 and MMP-9. Additionally, TPNs, serving as a multi-bioactive material, mitigates oxidative stress and inflammation, fosters M1-to-M2 repolarization of macrophages, and inhibits cell calcification and apoptosis. In experiments with AAA mice, TPNs-siRNA accumulated and persisted in aneurysmal tissue after intravenous delivery, demonstrating that TPNs-siRNA can be significantly distributed in macrophages and VSMCs relevant to AAA pathogenesis. Leveraging the carrier\'s intrinsic multi-bioactive properties, the targeted siRNA delivery by TPNs exhibits a synergistic effect for enhanced AAA therapy. Furthermore, TPNs-siRNA is gradually metabolized and excreted from the body, resulting in excellent biocompatibility. Consequently, TPNs emerges as a promising multi-bioactive nanotherapy and a targeted delivery nanocarrier for effective AAA therapy.