Abstract
Neutrophil membrane vesicles (NMVs) have been successfully applied to control the inflammatory cascade after spinal cord injury (SCI) by acting as an inflammatory factor decoy to front-load the overall inflammation regulatory window; however, the mechanisms by which NMVs regulate macrophage phenotypic shifts as well as their outcomes have rarely been reported. In this study, we demonstrated the "efferocytosis-like" effect of NMVs endocytosed by macrophages, supplementing the TCA cycle intermediate metabolite α-KG by promoting glutamine metabolism, which in turn facilitates oxidative phosphorylation and inhibits the NF-κB signaling pathway to reprogram inflammatory macrophages to the pro-regenerative phenotype. Based on these findings, a "Trojan horse" composite fiber scaffold was constructed; this comprised a carboxylated poly-l-lactic acid shell encapsulated with NMVs and a core loaded with brain-derived neurotrophic factor to spatiotemporally modulate the inflammatory microenvironment by 39.23% and sustainably promote nerve regeneration by 85.67%. In vivo experiments further confirmed the effect of NMV-coated fiber scaffolds on the regulation of early innate immune inflammation and the continuous promotion of nerve regeneration. This study not only further unravels the mechanism of neutrophil membrane-macrophage interactions but also provides a strategy for coordinating inflammatory reprogramming and nerve regeneration following SCI.