Biomimetic “Trojan Horse” Fibers Modulate Innate Immunity Cascades for Nerve Regeneration

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.