Peripheral nerve injury (PNI) is a common but complex traumatic disorder often resulting in sensory and motor dysfunction (Dong et al., 2025; Huo et al., 2025). After PNI, axons will undergo a complex repair process, including resealing the injured terminus, reconstructing the cytoskeleton, synthesizing and transporting building materials, assembling axonal components, and forming growth cones (He and Jin, 2016), all of which require energy in the form of adenosine triphosphate (ATP) (Han et al., 2020). However, due to mitochondrial damage caused by the axonal injury and the increased energy demands of the regenerative events, injured axons face a net energy deficit, leading to slow axonal regeneration (Au et al., 2022). Recent studies indicate that, under both basal and activated conditions, axonal terminals perform lower levels of aerobic glycolysis compared to the somatic compartment (Wei et al., 2023; Li et al., 2023; Yates, 2024). This metabolic characteristic suggests that enhancing neuronal aerobic glycolysis levels may contribute to rescue the energy deficit and promote axonal regeneration. PKM2 is a key regulatory enzyme in glycolysis. Compared with other pyruvate kinase isoforms, PKM2 exhibits relatively low enzymatic activity. This property leads to a distinct metabolic state with reduced oxygen consumption and enhanced lactate production. This shift supports both antioxidant defense and nucleotide biosynthesis (Anastasiou et al., 2011). LDHA catalyzes the conversion of pyruvate into lactate. Upregulation of LDHA has been shown to shift cellular energy metabolism away from mitochondrial oxidative phosphorylation toward aerobic glycolysis (Zheng et al., 2016).

In metabolism-based therapeutic interventions, plant derived bioenergetic components and nanovesicular carriers have attracted increasing attention. They can provide metabolic support while facilitating the delivery of metabolic signals, thereby influencing cellular metabolic processes. Chen et al. demonstrated that independent photosynthetic systems have been shown to supply ATP and NADPH under light irradiation, leading to improved cellular energy status and anabolic metabolism (Chen et al., 2022). Li et al. demonstrated that spinach-derived thylakoid structures enhance oxygen production and redox capacity to reshape inflammatory microenvironments(Li et al., 2025). These studies highlight plant-derived bioenergetic modules as a critical bridge linking energy supply, metabolic reprogramming, and tissue regeneration. Numerous studies have shown that plant-derived extracellular vesicles exhibited significant therapeutic effects, including restoring redox balance, mitigating inflammation, and promoting tissue regeneration (Di Raimo et al., 2024; Shi et al., 2025; Yang et al., 2025). These effects may result from extracellular vesicles efficiently delivering proteins, lipids, RNAs, and other bioactive cargos to diseased cells or tissues (Huang et al., 2025). In addition, extracellular vesicles derived from medicinal plants have been demonstrated to possess excellent biocompatibility and rich biological activity, showing great potential as therapeutics for treating various diseases.

Gastrodia elata has been reported to alleviate energy metabolic dysfunction and to exhibit antioxidant and neuroprotective effects (Ni et al., 2024; Ji et al., 2026). Based on these findings, we hypothesized that extracellular vesicles derived from Gastrodia elata (GEDEVs) may retain bioactive components capable of supporting nerve repair after PNI. In vivo, histological and functional analyses confirmed that GEDEVs significantly promote nerve regeneration. In vitro, myelin debris impaired axonal outgrowth and increased oxidative stress in DRG neurons. By contrast, GEDEVs treatment reduced oxidative stress and promoted neurite regeneration. Mechanistically, these effects were associated with increased expression of PKM2 and LDHA, suggesting a shift toward enhanced glycolytic activity. These findings indicated that GEDEVs can improve cellular bioenergetic status through glycolysis-related pathways, highlighting their potential as a plant-derived therapeutic approach for PNI.