Mechanoregulative hydrogel facilitates rapid scarless healing by self-adaptive control of wound niche at different stages

It is essential to spatiotemporally control the microniche of wound at different healing stages for rapid and scarless healing. Hence, a multifunctional soft hydrogel integrated with programmed drug release capability (MLVgel) was fabricated. MLVgel is adhesive and moldable with low friction response, which provides moisture and responses to an infectious environment to deliver bactericidal and antioxidant effects in rat bacterial infection and burn wound models. By release control, instant short-term inflammation suppression is combined with sustained mechano-transduction signal inhibition. This dynamically modulates immune responses and delays <i>En1</i>⁺ fibroblast activation via the YAP-TEAD pathway, ultimately facilitating scarless wound regeneration. Genomic analyses showed that the enhanced reepithelization and mechanoregulation by MLVgel during different wound phases are indispensable for its therapeutic outcomes. Last, MLVgel resulted in markedly improved healing in a pig mature scar model, which demonstrated its translation potential. Our results also verified the necessity of programed dynamic regulation in the healing process.