Axolotl skin mechanics–biomimetic hydrogel promotes scarless wound healing associated with macrophage polarisation via Piezo1/YAP signalling

Reduced wound mechanical tension or stiffness constitutes a critical mechanical microenvironment that promotes ordered scarless regeneration. However, existing clinical biomaterials are insufficient to modulate wound bed stiffness effectively. This study demonstrates that axolotl skin, which possesses an inherent capacity for ordered scarless wound regeneration, exhibits a significantly lower Young's modulus than mouse and human skin, which are characterized by disordered scar repair. Inspired by these cross-species regenerative mechanical characteristics, a series of hydrogels comprising silk fibroin methacryloyl (SFMA) and β-sheet-rich silk nanofibers (BSNF) was developed with identical architectures and tunable Young's moduli (1.79–139 kPa), achieved through pH modulation. These hydrogels biomimic three representative skin mechanical microenvironments: ordered regenerated tissue in axolotls ( E Regen -gel); disordered repaired tissue in mice ( E Norm -gel); and pathological scar tissue in humans ( E Scar -gel). The hydrogels remodelled the mechanical microenvironment of the wound bed and regulated wound healing, with E Regen -gel demonstrating superior efficacy in promoting scarless regeneration. This effect was evidenced by accelerated re-epithelialisation, ordered neovascularisation, formation of a basket-weave-like soft extracellular matrix (ECM) resembling unwounded normal skin, and robust regeneration of skin appendages. Mechanistic studies demonstrated that E Regen -gel promoted M2 macrophage polarisation by attenuating Piezo1/Yes-associated protein (YAP) mechanosignalling in macrophages during the early phase of wound healing, thereby modulating the wound immune microenvironment and establishing a favourable foundation for subsequent scarless wound regeneration. In conclusion, biomechanical modulation of the wound microenvironment using an axolotl skin mechanics–biomimetic hydrogel is sufficient to promote scarless wound regeneration. These findings provide a novel strategy for clinical wound repair based on mechanical microenvironment regulation.