Berberine-loaded M2 macrophage-derived exosomes for spinal cord injury therapy
Berberine-loaded M2 macrophage-derived exosomes for spinal cord injury therapy
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DOI：
10.1016/j.actbio.2021.03.018
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发表时间：
2021-04-29
影响因子：
9.7
通讯作者：
Wu, Chao
中科院分区：
文献类型：
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作者：
Gao, Zhan-Shan;Zhang, Chuan-Jie;Wu, Chao
脊髓损伤引起巨噬细胞/小胶质细胞的免疫激活。活化的巨噬细胞/小胶质细胞有两种不同的表型，促炎经典活化（M1）表型和抗炎替代活化（M2）表型。M1型巨噬细胞/小胶质细胞是炎症的关键因素。由于抗炎药物通过血脑屏障（BBB）的非靶向性和效率低下，脊髓损伤的治疗仍然是一个巨大的挑战。本实验的目的是设计m2型原代腹膜巨噬细胞外泌体（Exos）作为小檗碱（Ber）的药物载体，由于Exos跨越血脑屏障的天然优势，可以有效地靶向将药物递送到损伤的脊髓。采用超声负载法对粒径为125 +/- 12 nm的Exos进行负载，载药量达到17.13 +/- 1.64%。Ber释放实验表明，负载样品（Exos-Ber）具有缓释作用，48 h内累积释放量达到71.44±2.86%。体外和体内实验证实，Exos-Ber可降低M1蛋白标志物iNOS，升高M2蛋白标志物CD206，降低炎症和凋亡细胞因子（tnf - α、IL-1 β、IL-6、Caspase 9、Caspase 8）。表明Exos-Ber具有良好的抗炎和抗凋亡作用，可诱导巨噬细胞/小胶质细胞由M1表型向M2表型极化。此外，Exos-Ber治疗后，脊髓损伤小鼠的运动功能明显改善，表明Exos-Ber是一种潜在的脊髓损伤治疗药物。有效靶向给药策略的研究进展。除了良好的生物相容性和隐身能力外，M2巨噬细胞来源的外泌体还具有天然的炎症靶向能力。脊髓损伤后的炎症微环境为外泌体靶向提供了动力。天然药物载体，安全性更高。随着纳米材料的快速发展，药物载体的选择性越来越强。然而，由于中枢神经系统损伤后的特殊微环境，一些不可降解的无机材料会增加神经元自愈的压力，甚至对神经元造成二次损伤，外泌体的出现解决了这一问题。以往的一些研究使用肿瘤细胞系外泌体作为药物载体，但其自身携带的致癌因子具有极高的隐患，内源性巨噬细胞外泌体相对于其安全性具有绝对优势。(C) 2021材料学报Elsevier Ltd.出版。版权所有。
Spinal cord injury (SCI) causes immune activation of resident macrophages/microglia. Activated macrophages/microglia have two different phenotypes, the pro-inflammatory classically activated (M1) phenotype and the anti-inflammatory alternatively activated (M2) phenotype. M1 phenotype macrophages/microglia are the key factor in inflammation. The treatment of SCI remains a huge challenge due to the nontargeting and inefficiency of anti-inflammatory drugs through the blood-brain barrier (BBB). The purpose of this experiment was to design M2-type primary peritoneal macrophages exosomes (Exos) as a drug carrier for berberine (Ber), which can be efficiently targeted to deliver drugs to the injured spinal cord due to the natural advantage of Exos across the BBB. The Exos with particle size of 125 +/- 12 nm were loaded with by an ultrasonic method and the drug loading reached 17.13 +/- 1.64%. The Ber release experiment showed that the loaded sample (Exos-Ber) exhibited sustained release effect, and the cumulative release amount reached 71.44 +/- 2.86% within 48 h. In vitro and in vivo experiments confirmed that the Exos-Ber could decrease the M1 protein marker iNOS, elevate the M2 protein marker CD206 and reduce inflammatory and apoptotic cytokines (TNF-alpha, IL-1 beta, IL-6, Caspase 9, Caspase 8), which showed that Exos-Ber had a good anti-inflammatory and anti-apoptotic effect by inducing macrophages/microglia from the M1 phenotype to M2 phenotype polarization. Moreover, the motor function of SCI mice was significantly improved after Exos-Ber treatment, indicating that Exos-Ber is a potential agent for SCI therapy.Statement of significanceEfficient targeting strategy for drug delivery. In addition to good biocompatibility and stealth ability, M2 macrophage-derived Exosomes present natural inflammatory targeting ability. The inflammatory microenvironment after spinal cord injury provides motivation for the targeting of exosomes.Natural drug carrier with higher safety. With the rapid development of nanomaterials, drug carriers have become more selective. However, due to the special microenvironment after central nervous system damage, some non-degradable inorganic materials will increase the pressure of self-healing and even secondary damage to neurons, which has been solved by the emergence of exosomes. Some previous studies used tumor cell line exosomes as drug carriers, but the carcinogenic factors carried by themselves have extremely high hidden dangers, and endogenous macrophage exosomes have absolute advantages over their safety. (C) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.