Local Delivery of Dual Stem Cell-Derived Exosomes Using an Electrospun Nanofibrous Platform for the Treatment of Traumatic Brain Injury.

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.