A gelatin methacryloyl (GelMA)-based biomimetic melatonin/vascular endothelial growth factor-encoding plasmid (pVEGF) nerve conduit regulates the early redox-angiogenic microenvironment for long-gap peripheral nerve repair.

Biological macromolecule-derived matrices and biomimetic delivery interfaces can convert artificial nerve conduits from passive bridges into locally regulatory repair platforms. Long-gap peripheral nerve defects remain difficult to repair because the defect region must rapidly rebuild a vascularized, cytoprotective, and cell-permissive microenvironment for Schwann cell survival, axonal extension, and remyelination. Here, we developed a Gelatin Methacryloyl (GelMA)-based biomimetic melatonin/vascular endothelial growth factor (VEGF)-encoding plasmid DNA (pVEGF) Polycaprolactone (PCL)/GelMA nerve conduit incorporating macrophage membrane-coated nanoparticles (MNPs). In this hierarchical design, PCL provided structural support, GelMA formed a gelatin-derived intraluminal hydrogel matrix, and MNPs served as the integrated melatonin/pVEGF delivery module. The nanoparticles showed stable assembly, sustained dual-cargo release, and retention of macrophage membrane-associated proteins. In vitro, the system enhanced VEGF expression, promoted endothelial migration and tube formation, reduced oxidative stress, and protected Schwann cells under oxidative injury. In a rat 15-mm sciatic nerve defect model, the PCL-G@MNPs conduit improved early vascular reconstruction, axon/Schwann cell-associated tissue regeneration, remyelination, electrophysiological recovery, target muscle preservation, and sensory-motor functional outcomes compared with control conduits. Bulk RNA sequencing (RNA-seq) further identified early enrichment of antioxidant-response, hypoxia-inducible factor-1 (HIF-1)/VEGF-related angiogenic, extracellular matrix/cell-adhesion, and neurotrophic programs. These molecular changes were observed together with later structural and functional improvements, although the temporal and causal relationships among redox regulation, vascular remodeling, neural regeneration, and functional recovery were not directly established. These findings support the integration of biological macromolecular matrices, membrane-biomimetic interfaces, and nucleic-acid delivery as a redox-angiogenic microenvironmental priming strategy for long-gap peripheral nerve repair.