Aligned PCL conduits integrated with tranilast-loaded GelMA hydrogel for immune-regulated peripheral nerve regeneration

Effective peripheral nerve repair requires coordinated topographical guidance, remyelination, and immune microenvironment remodeling within nerve guidance conduits. However, conventional conduits often provide passive bridging with limited inflammatory regulation. Here, we developed a tranilast-loaded gelatin methacryloyl (GelMA) hydrogel-filled aligned polycaprolactone (PCL) conduit (H-TG) by integrating high-speed-collected electrospun PCL fibers with a locally immunomodulatory hydrogel. The aligned PCL conduit provided ordered physical cues that enhanced neuronal-like PC12 cell responses and rat Schwann cell (RSC) adhesion, spreading, and regeneration-associated marker expression in vitro. Meanwhile, under H₂O₂ exposure, tranilast reduced CD86 and iNOS expression and increased Arg1 and CD206 expression, indicating a shift toward a reparative macrophage-associated phenotype. In a rat 10 mm sciatic nerve defect model, H-TG promoted functional recovery, axonal regeneration, and remyelination, reduced the g-ratio, attenuated gastrocnemius muscle atrophy, and improved nerve histomorphology. Furthermore, H-TG decreased CD68⁺iNOS⁺ M1-like macrophages and TNF-α expression while increasing CD68⁺CD206⁺ M2-like macrophages and IL-10 expression. These findings support an aligned and immunomodulatory conduit strategy for peripheral nerve regeneration.