Severe skin injuries require scaffolds capable of dynamically regulating cell migration and proliferation to accelerate wound closure and tissue regeneration. However, most existing strategies rely on a single mode of guidance and fail to recapitulate the coordinated spatiotemporal cues present in native healing environments. Here, we report a graded nanofiber scaffold that integrates biophysical and biochemical cues to provide topographic, haptotactic, and chemotactic signals for promoting efficient skin repair. The scaffold is composed of radially aligned poly(ε-caprolactone) nanofibers surface-deposited with epidermal growth factor (EGF)-loaded collagen nanoparticles in a radial density gradient, fabricated via coaxial electrospraying. This design enables sustained release of bioactive EGF for up to 10 days while guiding cell migration toward the wound center. In vitro studies demonstrated enhanced directional migration and proliferation of keratinocytes and fibroblasts. Transcriptomic analysis revealed activation of cytoskeletal remodeling, membrane fluidity regulation, and integrin-mediated adhesion pathways, highlighting the scaffold's role in orchestrating cell motility. In a full-thickness rat skin injury model, the scaffold accelerated wound closure, enhanced cell proliferation, and promoted collagen deposition, resulting in skin wound healing. This study presents a simple and versatile platform for delivering spatially graded cues, offering strong potential for clinical translation and extension to other tissue regeneration applications.
