Transplantation　of　olfactory　ensheathing　cells　(OECs)　has　been　demonstrated　to　be　beneficial　for　spinal　cord　injury　(SCI)　by　modulating　neuroinflammation,　supporting　neuronal　survival　and　promoting　angiogenesis.　Besides　OECs,　the　conditioned　medium　(CM)　from　OECs　has　also　been　proved　to　have　therapeutic　effects　for　SCI,　indicating　that　the　bioactive　substances　secreted　by　OECs　are　essential　for　its　protective　effects.　Nevertheless,　there　is　still　little　information　regarding　the　underlying　mechanisms.　Considering　that　exosomes　are　crucial　for　intercellular　communication　and　could　be　secreted　by　different　types　of　cells,　we　speculated　that　the　therapeutic　potential　of　OECs　for　SCI　might　be　partially　based　on　their　exosomes.　To　examine　whether　OECs　could　secret　exosomes,　we　isolated　exosomes　by　polyethylene　glycol-based　method,　and　identified　them　by　electron　microscopy　study,　nanoparticle　tracking　analysis　(NTA)　and　western　blotting.　In　view　of　phagocytic　ability　of　microglia　and　its　distinct　roles　in　microenvironment　regulation　after　SCI,　we　then　focused　the　effects　of　OECs-derived　exosomes　(OECs-Exo)　on　microglial　phenotypic　regulation.　We　found　that　the　extracted　OECs-Exo　could　be　engulfed　by　microglia　and　partially　reverse　the　LPS-induced　pro-inflammatory　polarization　through　inhibiting　NF-κB　and　c-Jun　signaling　pathways　in　vitro.　Furthermore,　OECs-Exo　were　found　to　inhibit　the　polarization　of　pro-inflammatory　macrophages/microglia　while　increased　the　numbers　of　anti-inflammatory　cells　after　SCI.　Considering　that　the　neuronal　injury　is　closely　related　to　the　activation　state　of　macrophages/microglia,　co-culture　of　microglia　and　neurons　were　performed.　Neuronal　death　induced　by　LPS-treated　microglia　could　be　significantly　alleviated　when　microglia　treated　by　LPS　plus　OECs-Exo　in　vitro.　After　SCI,　NeuN-immunostaining　and　axonal　tract-tracing　were　performed　to　assess　neuronal　survival　and　axon　preservation.　Our　data　showed　that　the　OECs-Exo　promoted　the　neuronal　survival　and　axon　preservation,　and　facilitated　functional　recovery　after　SCI.　Our　findings　provide　a　promising　therapeutic　strategy　for　SCI　based　on　exosome-immunomodulation.　©　2021　The　Authors.　Bioengineering　&　Translational　Medicine　published　by　Wiley　Periodicals　LLC　on　behalf　of　The　American　Institute　of　Chemical　Engineers.