Department of Orthopedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
Department of Orthopedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.
Int J Pharm. 2023 Aug 25;643:123283. doi: 10.1016/j.ijpharm.2023.123283. Epub 2023 Aug 1.
After spinal cord injury (SCI), local inflammatory response and fibrous scar formation severely hinder nerve regeneration. Berberine (Ber) has a powerful regulatory effect on the local microenvironment, but its limited solubility and permeability through the blood-brain barrier severely limit its systemic efficacy. Human umbilical cord mesenchymal stem cells (hUC-MSCs)-derived small extracellular vesicles (sEVs) are natural nanocarriers with high cargo loading capacity, and can cross the blood-brain barrier. Most importantly, sEVs can improve drug solubility and drug utilization. Therefore, they can overcome many defects of Ber application. This experiment aimed to design a Ber-carrying hUC-MSCs-derived sEVs and GelMA hydrogel. Ber was loaded into sEVs (sEVs-Ber) by ultrasonic co-incubation with a drug loading capacity (LC) of 15.07%. The unhindered release of up to 80% of sEVs-Ber from GelMA hydrogel was accomplished for up to 14 days. And they could be directly absorbed by local cells of injury, allowing for direct local delivery of the drug and enhancing its efficacy. The experimental results confirmed injecting GelMA-sEVs-Ber into spinal cord defects could exert anti-inflammatory effects by regulating the expression of inflammatory factors. It also demonstrated the anti-fibrotic effect of Ber in SCI for the first time. The modulatory effects of sEVs and Ber on the local microenvironment significantly promoted nerve regeneration and recovery of motor function in post-SCI rats. These results demonstrated that the GelMA-sEVs-Ber dual carrier system is a promising therapeutic strategy for SCI repair.
脊髓损伤（SCI）后，局部炎症反应和纤维瘢痕形成严重阻碍神经再生。小檗碱（Ber）对局部微环境具有强大的调节作用，但由于其在血液-脑屏障中的溶解度和通透性有限，严重限制了其全身疗效。人脐带间充质干细胞（hUC-MSCs）衍生的小细胞外囊泡（sEVs）是具有高载药能力的天然纳米载体，可穿透血脑屏障。最重要的是，sEVs 可以提高药物的溶解度和利用率。因此，它们可以克服 Ber 应用的许多缺陷。本实验旨在设计一种载有小檗碱的 hUC-MSCs 衍生的 sEVs 和 GelMA 水凝胶。通过超声共孵育将小檗碱装载到 sEVs 中（sEVs-Ber），载药能力（LC）为 15.07%。多达 80%的 sEVs-Ber 可以在 GelMA 水凝胶中无阻碍地释放长达 14 天。并且它们可以被损伤部位的局部细胞直接吸收，从而可以直接局部给药，增强疗效。实验结果证实，将 GelMA-sEVs-Ber 注射到脊髓缺损部位可以通过调节炎症因子的表达发挥抗炎作用。这也是首次证明小檗碱在 SCI 中的抗纤维化作用。sEVs 和 Ber 对局部微环境的调节作用显著促进了 SCI 后大鼠的神经再生和运动功能恢复。这些结果表明，GelMA-sEVs-Ber 双载体系统是一种很有前途的 SCI 修复治疗策略。
