Neurotrophic factors, particularly nerve growth factor, enhance neuronal regeneration. However, the in vivo applications of nerve growth factor are largely limited by its intrinsic disadvantages, such as its short biological half-life, its contribution to pain response, and its inability to cross the blood-brain barrier. Considering that let-7 (human miRNA) targets and regulates nerve growth factor, and that let-7 is a core regulator in peripheral nerve regeneration, we evaluated the possibilities of let-7 application in nerve repair. In this study, anti-let-7a was identified as the most suitable let-7 family molecule by analyses of endogenous expression and regulatory relationship, and functional screening. Let-7a antagomir demonstrated biosafety based on the results of in vivo safety assessments and it entered into the main cell types of the sciatic nerve, including Schwann cells, fibroblasts and macrophages. Use of hydrogel effectively achieved controlled, localized, and sustained delivery of let-7a antagomir. Finally, let-7a antagomir was integrated into chitosan conduit to construct a chitosan-hydrogel scaffold tissue-engineered nerve graft, which promoted nerve regeneration and functional recovery in a rat model of sciatic nerve transection. Our study provides an experimental basis for potential in vivo application of let-7a.

中文翻译：

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let-7a 拮抗剂在受损周围神经再生中的潜在应用。

神经营养因子，特别是神经生长因子，增强神经元再生。然而，神经生长因子的体内应用在很大程度上受到其固有缺点的限制，例如其生物半衰期短、对疼痛反应的贡献以及无法穿过血脑屏障。考虑到 let-7（人类 miRNA）靶向并调节神经生长因子，并且 let-7 是周围神经再生的核心调节因子，我们评估了 let-7 在神经修复中应用的可能性。本研究通过内源性表达调控关系分析、功能筛选，确定anti-let-7a为最合适的let-7家族分子。Let-7a antagomir 基于体内安全性评估结果证明了生物安全性，它进入了坐骨神经的主要细胞类型，包括雪旺细胞、成纤维细胞和巨噬细胞。使用水凝胶有效地实现了 let-7a 拮抗剂的受控、局部和持续递送。最后，将let-7a antagomir整合到壳聚糖导管中，构建了壳聚糖-水凝胶支架组织工程神经移植物，促进了大鼠坐骨神经横断模型的神经再生和功能恢复。我们的研究为 let-7a 的潜在体内应用提供了实验基础。将let-7a antagomir整合到壳聚糖导管中构建壳聚糖-水凝胶支架组织工程神经移植物，促进坐骨神经横断大鼠模型的神经再生和功能恢复。我们的研究为 let-7a 的潜在体内应用提供了实验基础。将let-7a antagomir整合到壳聚糖导管中构建壳聚糖-水凝胶支架组织工程神经移植物，促进坐骨神经横断大鼠模型的神经再生和功能恢复。我们的研究为 let-7a 的潜在体内应用提供了实验基础。