Biomimetic “Trojan\nHorse” Fibers Modulate\nInnate Immunity Cascades for\nNerve Regeneration

Neutrophil membrane vesicles (NMVs) have been successfully\napplied\nto control the inflammatory cascade after spinal cord injury (SCI)\nby acting as an inflammatory factor decoy to front-load the overall\ninflammation regulatory window; however, the mechanisms by which NMVs\nregulate macrophage phenotypic shifts as well as their outcomes have\nrarely been reported. In this study, we demonstrated the “efferocytosis-like”\neffect of NMVs endocytosed by macrophages, supplementing the TCA cycle\nintermediate metabolite α-KG by promoting glutamine metabolism,\nwhich in turn facilitates oxidative phosphorylation and inhibits the\nNF-κB signaling pathway to reprogram inflammatory macrophages\nto the pro-regenerative phenotype. Based on these findings, a “Trojan\nhorse” composite fiber scaffold was constructed; this comprised\na carboxylated poly-l-lactic acid shell encapsulated with\nNMVs and a core loaded with brain-derived neurotrophic factor to spatiotemporally\nmodulate the inflammatory microenvironment by 39.23% and sustainably\npromote nerve regeneration by 85.67%. In vivo experiments further\nconfirmed the effect of NMV-coated fiber scaffolds on the regulation\nof early innate immune inflammation and the continuous promotion of\nnerve regeneration. This study not only further unravels the mechanism\nof neutrophil membrane–macrophage interactions but also provides\na strategy for coordinating inflammatory reprogramming and nerve regeneration\nfollowing SCI.