3D printing of interferonγ-preconditioned NSC-derived exosomes/collagen/chitosan biological scaffolds for neurological recovery after TBI

The reconstruction of neural function and recovery of chronic damage following traumatic brain injury(TBI)remain significant clinical challenges.Exosomes derived from neural stem cells(NSCs)offer various benefits inTBI treatment.Numerous studies confirmed that appropriate preconditioning methods enhanced the targetedefficacy of exosome therapy.Interferon-gamma(IFN-γ)possesses immunomodulatory capabilities and is widelyinvolved in neurological disorders.In this study,IFN-γwas employed for preconditioning NSCs to enhance theefficacy of exosome(IFN-Exo,IE)for TBI.miRNA sequencing revealed the potential of IFN-Exo in promotingneural differentiation and modulating inflammatory responses.Through low-temperature 3D printing,IFN-Exowas combined with collagen/chitosan(3D-CC-IE)to preserve the biological activity of the exosome.The deliveryof exosomes via biomaterial scaffolds benefited the retention and therapeutic potential of exosomes,ensuring that they could exert long-term effects at the injury site.The 3D-CC-IE scaffold exhibited excellentbiocompatibility and mechanical properties.Subsequently,3D-CC-IE scaffold significantly improved impairedmotor and cognitive functions after TBI in rat.Histological results showed that 3D-CC-IE scaffold markedlyfacilitated the reconstruction of damaged neural tissue and promoted endogenous neurogenesis.Furthermechanistic validation suggested that IFN-Exo alleviated neuroinflammation by modulating the MAPK/mTORsignaling pathway.In summary,the results of this study indicated that 3D-CC-IE scaffold engaged in long-termpathophysiological processes,fostering neural function recovery after TBI,offering a promising regenerativetherapy avenue.