Fecha de publicación: -- Fuente: PubMed "nature biotechnology" Bioact Mater. 2026 Oct 31;70:44-63. doi: 10.1016/j.bioactmat.2026.10.030. eCollection 2027 Apr.ABSTRACTBACKGROUND: Clinical translation of stem cell-derived small extracellular vesicles (sEVs) for traumatic brain injury (TBI) is restricted by low yield in 2D culture and rapid in vivo clearance.OBJECTIVE: To develop an in situ sustained delivery system (3D-sEVs@Gel) encapsulating 3D-bioprinted adipose stem cell (ADSC)-derived sEVs (3D-ADSC-sEVs) within GelMA (Gelatin methacryloyl) hydrogel for long-term functional repair after TBI.METHODS: SEVs derived from coaxially bioprinted 3D-ADSCs were isolated, and a GelMA hydrogel-based delivery system was subsequently constructed. Following orthotopic transplantation of the 3D-sEVs@Gel system into the lesion site after TBI, functional recovery, neural stem cell (NSC) proliferation and lineage-associated responses, and the underlying molecular mechanisms were systematically evaluated through behavioral tests, immunofluorescence, multi-omics, and pharmacological inhibition.RESULTS: SEVs generated using the coaxial alginate-microfiber culture system exhibited an approximately eightfold higher yields and protein loading compared with those obtained from 2D culture. In vivo, 3D-sEVs@Gel prolonged local retention, reduced tissue loss, and significantly improved long-term sensorimotor coordination and spatial memory following TBI. In addition, treatment increased the numbers of proliferating cells co-expressing neural progenitor-, neuronal-, and oligodendroglial-lineage-associated markers within the examined neurogenic regions. Mechanistically, 3D-sEV treatment increased nuclear CREB1 levels in NSCs, promoting PGC-1α transcription and subsequent FNDC5 expression, thereby supporting endogenous neurogenesis and functional neural repair.CONCLUSION: The 3D-sEVs@Gel system promotes chronic neurological reconstruction post-TBI by modulating NSC proliferation and neural lineage-associated responses through the CREB1/PGC-1α/FNDC5 pathway, offering a promising cell-free strategy for neural repair and tissue engineering.PMID:42999541 | PMC:PMC13743902 | DOI:10.1016/j.bioactmat.2026.10.030