Zhang Xunqi, Cao Jian, Wu Jiahe, Mu Jiafu, Huang Tianchen, Zheng Juanjuan, Guo Jing, Zhu Manning, Feng Shiqing, Gao Jian-Qing
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China.
Int J Pharm. 2025 Feb 25;671:125222. doi: 10.1016/j.ijpharm.2025.125222. Epub 2025 Jan 13.
Intense inflammatory responses and elevated levels of reactive oxygen species (ROS) extremely exacerbate the pathological process of spinal cord injury (SCI). Mesenchymal stem cell (MSC)-derived extracellular vesicles (EV) can mitigate SCI-related inflammation but their production yield remains limited. Alternatively, MSC-extruded nanovesicles (NV) inherit the therapeutic potential from MSCs and have a markedly higher yield than EV. In the present study, a bio-responsive scaffold system (RS+NV) was created for SCI treatment. NV was generated from human MSCs by physical extrusion and encapsulated in a ROS-responsive scaffold (RS). RS+NV efficiently scavenged environmental ROS and underwent degradation, thus facilitating the responsive release of NV. NV inhibited the pro-inflammatory phenotypic transformation, and reduced the secretion of TNF-α and IL-6 from lipopolysaccharide-stimulated BV2 cells, exhibiting comparable anti-inflammatory properties to EV. Additionally, NV posed a superior antioxidative effect than EV and could effectively alleviate the oxidative stress damage of HO-stimulated PC12 cells. Furthermore, in SCI rats, the uptake of NV was primarily attributed to microglia and neurons. RS+NV exhibited synergistic effects in regulating the hostile microenvironment in vivo during the acute phase, thereby establishing a conducive environment for long-term locomotor, tissue repair, and recovery of neuropathic pain. Overall, RS+NV shows promising potential for use as an anti-inflammatory and antioxidative therapeutic approach for treating SCI.
强烈的炎症反应和活性氧（ROS）水平升高会极大地加剧脊髓损伤（SCI）的病理过程。间充质干细胞（MSC）衍生的细胞外囊泡（EV）可以减轻SCI相关的炎症，但它们的产量仍然有限。另外，MSC挤出的纳米囊泡（NV）继承了MSC的治疗潜力，并且产量明显高于EV。在本研究中，创建了一种生物响应性支架系统（RS + NV）用于SCI治疗。通过物理挤压从人MSC产生NV，并将其封装在ROS响应性支架（RS）中。RS + NV有效地清除了环境中的ROS并发生降解，从而促进了NV的响应性释放。NV抑制促炎表型转化，并减少脂多糖刺激的BV2细胞中TNF-α和IL-6的分泌，表现出与EV相当的抗炎特性。此外，NV比EV具有更强的抗氧化作用，并且可以有效减轻HO刺激的PC12细胞的氧化应激损伤。此外，在SCI大鼠中，NV的摄取主要归因于小胶质细胞和神经元。RS + NV在急性期对体内敌对微环境的调节中表现出协同作用，从而为长期运动、组织修复和神经性疼痛的恢复建立了有利环境。总体而言，RS + NV作为治疗SCI的抗炎和抗氧化治疗方法显示出有前景的潜力。
