Department of ORL-HNS, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai 200070, China.
ACS Appl Mater Interfaces. 2024 Jul 24;16(29):37497-37512. doi: 10.1021/acsami.4c05004. Epub 2024 Jul 9.
Traumatic brain injury poses serious physical, psychosocial, and economic threats. Although systemic administration of stem cell-derived exosomes has recently been proven to be a promising modality for traumatic brain injury treatment, they come with distinct drawbacks. Luckily, various biomaterials have been developed to assist local delivery of exosomes to improve the targeting of organs, minimize nonspecific accumulation in vital organs, and ensure the protection and release of exosomes. In this study, we developed an electrospun nanofibrous scaffold to provide sustained delivery of dual exosomes derived from mesenchymal stem cells and neural stem cells for traumatic brain injury treatment. The electrospun nanofibrous scaffold employed a functionalized layer of polydopamine on electrospun poly(ε-caprolactone) nanofibers, thereby enhancing the efficient incorporation of exosomes through a synergistic interplay of adhesive forces, hydrogen bonding, and electrostatic interactions. First, the mesenchymal stem cell-derived exosomes and the neural stem cell-derived exosomes were found to modulate microglial polarization toward M2 phenotype, play an important role in the modulation of inflammatory responses, and augment axonal outgrowth and neural repair in PC12 cells. Second, the nanofibrous scaffold loaded with dual stem cell-derived exosomes (Duo-Exo@NF) accelerated functional recovery in a murine traumatic brain injury model, as it mitigated the presence of reactive astrocytes and microglia while elevating the levels of growth associated protein-43 and doublecortin. Additionally, multiomics analysis provided mechanistic insights into how dual stem cell-derived exosomes exerted its therapeutic effects. These findings collectively suggest that our novel Duo-Exo@NF system could function as an effective treatment modality for traumatic brain injury using sustained local delivery of dual exosomes from stem cells.
创伤性脑损伤会带来严重的身体、心理社会和经济威胁。虽然最近已经证明，干细胞衍生的外体的系统给药是治疗创伤性脑损伤的一种很有前途的方式，但它们也有明显的缺点。幸运的是，已经开发出各种生物材料来辅助外体的局部递送，以提高器官的靶向性，最小化在重要器官中的非特异性积累，并确保外体的保护和释放。在这项研究中，我们开发了一种电纺纳米纤维支架，以提供源自间充质干细胞和神经干细胞的双重外体的持续递送，用于治疗创伤性脑损伤。电纺纳米纤维支架在电纺聚己内酯纳米纤维上使用了功能化的聚多巴胺层，从而通过粘附力、氢键和静电相互作用的协同作用，增强了外体的有效掺入。首先，发现间充质干细胞衍生的外体和神经干细胞衍生的外体调节小胶质细胞向 M2 表型极化，在外体对炎症反应的调节中发挥重要作用，并增强 PC12 细胞中的轴突生长和神经修复。其次，负载双重干细胞衍生外体（Duo-Exo@NF）的纳米纤维支架在小鼠创伤性脑损伤模型中加速了功能恢复，因为它减轻了反应性星形胶质细胞和小胶质细胞的存在，同时提高了生长相关蛋白-43 和双皮质素的水平。此外，多组学分析提供了关于双重干细胞衍生外体发挥治疗作用的机制见解。这些发现共同表明，我们的新型 Duo-Exo@NF 系统可以作为一种有效的治疗方法，通过持续局部递送来自干细胞的双重外体来治疗创伤性脑损伤。
