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. Biomaterials are widely used in wound care, but whether they can actively direct tissue repair remains not well understood. Here, authors show that silk fibroin intrinsically programs keratinocytes into a regenerative state that coordinates epidermal–dermal crosstalk and promotes wound healing.