Injectable Carbon Nanotube-Functionalized Hydrogel for miRNA Delivery

摘要 MicroRNAs(MiRNAs)已被证明能促进心肌梗死后的心脏再生。然而， 目前的miRNA传递方法，如病毒载体或脂类制剂，对 广泛使用。我们已经开发出一种可注射的碳官能化温度响应型水凝胶。 用于传递miRNAs的纳米管(RTG-CNT)。RTG-CNT水凝胶由液-液转变为 在达到体温后不久，允许液体递送的凝胶基质迅速紧随其后 通过稳定凝胶miRNA定位。此外，这种水凝胶还改善了短期(8周)的生物相容性 与病毒和脂类方法相比，它促进miRNA的表达是脂类制剂的两倍。 在这项研究中，我们建议检验我们的新型RTG-CNT水凝胶远远优越的假设 MiRNAs到心脏的传递模式，通过提高生物相容性、靶向传递和更高 与病毒和脂类方法比较时，miRNA的表达。我们将通过一个 细胞生物学和生物工程的结合通过1)量化生物相容性和改进的程度 我们的RTG-CNT-miRNA递送系统通过脂质体和病毒载体的定位，2)测量 作为促再生miRNA递送系统的RTG-CNT水凝胶与脂质体和 病毒载体在小鼠心肌梗死模型中的传递和3)确定RTG-CNT水凝胶的传递潜力 抗纤维化miRNAs可进一步改善小鼠心肌梗死模型的心肌结构和挽救功能。我们 相信RTG-CNT水凝胶将提供更好的生物相容性和更高效的miRNA输送系统 与传统方法相比，这可以实际地转化为临床应用。

ABSTRACT microRNAs (miRNAs) have been proven to promote cardiac regeneration after myocardial infarction. However, current miRNA delivery methods, such as viral vectors or lipid formulations, present safety concerns for widespread use. We have developed an injectable thermo-responsive hydrogel functionalized with carbon nanotubes (RTG-CNT) for the delivery of miRNAs. The RTG-CNT hydrogel transitions from a liquid-solution to a gel-based matrix shortly after reaching body temperature allowing for a liquid-based delivery rapidly followed by a stable-gel miRNA localization. Moreover, this hydrogel has improved short-term (8-week) biocompatibility compared to viral and lipid approaches and it promotes two-fold more miRNA expression than lipid formulations. In this investigation, we propose to test the hypothesis that our novel RTG-CNT hydrogel is far superior delivery model of miRNAs to the heart, through increased biocompatibility, targeted delivery and higher miRNA expression when compared to viral and lipid approaches. We will address our hypothesis with a combination of cell biology and bioengineering by 1) Quantify the biocompatibility and the magnitude of improved localization of our RTG-CNT-miRNA delivery system over liposomal and viral vectors approaches, 2) Measure the improved efficiency of the RTG-CNT hydrogel as pro-regenerative miRNA delivery system vs. liposomal and viral vector deliveries in a mouse MI model and 3) Determine the potential of the RTG-CNT hydrogel to deliver anti-fibrotic miRNAs to further improve myocardial structure and rescue function in a mouse MI model. We believe that the RTG-CNT hydrogel will offer a more biocompatible and far more efficient miRNA delivery system than traditional approaches, that can be realistically translated into clinical applications.