Extracellular Matrix‐Mimetic Immunomodulatory Hydrogel for Accelerating Wound Healing

Abstract Macrophages play a crucial role in the complete processes of tissue repair and regeneration, and the activation of M2 polarization is an effective approach to provide a pro‐regenerative immune microenvironment. Natural extracellular matrix (ECM) has the capability to modulate macrophage activities via its molecular, physical, and mechanical properties. Inspired by this, an ECM‐mimetic hydrogel strategy to modulate macrophages via its dynamic structural characteristics and bioactive cell adhesion sites is proposed. The LZM‐SC/SS hydrogel is in situ formed through the amidation reaction between lysozyme (LZM), 4‐arm‐PEG‐SC, and 4‐arm‐PEG‐SS, where LZM provides DGR tripeptide for cell adhesion, 4‐arm‐PEG‐SS provides succinyl ester for dynamic hydrolysis, and 4‐arm‐PEG‐SC balances the stability and dynamics of the network. In vitro and subcutaneous tests indicate the dynamic structural evolution and cell adhesion capacity promotes macrophage movement and M2 polarization synergistically. Comprehensive bioinformatic analysis further confirms the immunomodulatory ability, and reveals a significant correlation between M2 polarization and cell adhesion. A full‐thickness wound model is employed to validate the induced M2 polarization, vessel development, and accelerated healing by LZM‐SC/SS. This study represents a pioneering exploration of macrophage modulation by biomaterials’ structures and components rather than drug or cytokines and provides new strategies to promote tissue repair and regeneration.