Dynamic matrix engineering promotes nascent protein deposition to drive cell migration and expedite Re-epithelization in chronic wound

Chronic wound healing remains a formidable clinical challenge, fundamentally hindered by stalled re-epithelialization caused by dysfunctional cell migration arising from a disordered mechano-biochemical microenvironment. Current therapeutic strategies relying on externally-assisted growth factors or mechanical stimulation often neglect the inherent capacity of the native, dynamic extracellular matrix (ECM) to govern cell behavior, specifically its viscoelasticity. By engineering a reversible hydrazone-crosslinked lysozyme-polyethylene glycol (LZM-PEG) dynamic hydrogel, we elucidated the mechanism whereby enhanced network dynamics activate early cell mechanotransduction via the integrin-FAK signaling axis, promoting nascent protein deposition which subsequently drives directed cell migration. Importantly, this mechano-biological effect exhibits distinct network dynamics dependence, as evidenced by the complete abolition of cell migration upon network rigidification, suggesting that matrix network dynamics constitutes a key regulatory factor. Diabetic mouse models demonstrated that this dynamic hydrogel accelerates chronic wound re-epithelialization by driving epithelial cell migration, solely by recapitulating ECM dynamics without exogenous interventions. This therapeutic effect reveals that the intrinsic mechano-bioactivity embedded in hydrogel's dynamic network can accelerate tissue repair by modulating in situ cell behavior. Collectively, this study uncovers a mechano-biological axis: matrix dynamics-nascent protein deposition-cell migration, which provides mechanobiological insights into tissue repair, and offers a novel “materiobiology” design strategy for next-generation regenerative materials. • A reversible hydrazone-crosslinked LZM-PEG hydrogel was engineered with independently tunable viscoelasticity to mimic ECM-like dynamic mechanical behavior. • Dynamic network behavior activates integrin–FAK mechanotransduction, triggering nascent protein deposition and directional cell migration. • Matrix rigidification abolishes migration, highlighting hydrogel network dynamics as a key regulator of epithelial cell behavior. • The dynamic hydrogel promotes re-epithelialization in diabetic wounds without exogenous biochemical or physical stimuli. • This study reveals a matrix dynamics–protein deposition–cell migration axis, offering a materiobiological strategy for regenerative material design.