Pro‐Regenerative Glycopeptide Hydrogel Activates Type 2 Immune Response for Wound Healing via Macrophage‐T Cell Crosstalk

Abstract Immunomodulatory biomaterials are increasingly used in regenerative medicine. Biomimetic glycopeptide hydrogel is found to accelerate cutaneous wound healing by inducing macrophage M2‐type polarization, however, it is unclear whether this will possibly orchestrate a pro‐regenerative T cell immunity. Here the aim of this study is to elucidate the reparative T‐cell immune response in tissue regeneration by augmenting macrophage‐T cell crosstalk with a novel immunomodulatory glycopeptide hydrogel (termed as GRK^gel) self‐assembled by mannose receptor‐binding glucomannan (GM) chemically grafted with RADA16‐conjugated T‐cell epitope. The glycopeptide can be phagocytized and processed by macrophages, which then presents peptides to naïve T cells and polarizes them into T helper 2 (T_H2) cells through IL‐4‐dependent STAT6/GATA3 or c‐Maf pathways. Strikingly, full‐thickness skin wound repair in mice indicates a superior efficacy of GRK^gel on restoring the pathological structure and hair follicle by provoking T_H2 immune response, increasing the residence of M2 macrophages, as well as promoting angiogenesis at the local tissue environment. Furthermore, genomics results illustrates the role of GRK^gel serving as an immunomodulatory niche, orchestrating immune cell crosstalk and promoting extracellular matrix (ECM) reconstruction. Collectively, this study highlights the significance of crosstalk between immune cells in evoking pro‐healing T‐cell immunity, providing a promising drug‐/cytokine‐free strategy for endogenous tissue regeneration.