Silk fibroin intrinsically activates Ccl27⁺ migratory-paracrine keratinocytes to orchestrate epidermal–dermal crosstalk for regenerative wound healing

Rapid and functional skin wound healing remains a major clinical challenge, while current biomaterial-based therapies largely serve as passive scaffolds or delivery vehicles. Whether biomaterials possess intrinsic bioactivities that instruct endogenous regenerative programs remains unclear. Here, independent of bulk structural/mechanical cues or exogenous biomolecules, we show that silk fibroin (SF), a clinically approved biomaterial, intrinsically programs keratinocytes into a Ccl27⁺ migratory-paracrine pro-regenerative state that coordinates epidermal-dermal crosstalk to drive regenerative wound healing. Integrated scRNA-seq, proteomics, and genetic perturbation reveal that SF engages keratinocyte ITGA2 to activate PI3K-Akt signaling and relieve P53-mediated Ccl27 repression. Elevated Ccl27 enhances keratinocyte migration and re-epithelialization, while its secretion from SF-activated keratinocytes promotes fibroblast proliferation and dermal remodeling, collectively enabling wound closure and appendage reconstruction. Keratinocyte-specific Ccl27 knockdown largely abrogates SF-mediated regeneration in vivo. These findings uncover the intrinsic bioactivity of SF and establish biomaterials as instructive cues rather than passive scaffolds for functional tissue repair.