LA-peptide Hydrogel—Regulation of macrophage and fibroblast fates and their crosstalk via attenuating TGF-β to promote scarless wound healing

The homeostasis of the wound microenvironment is fundamental for scarless wound healing, while the excessive accumulation of transforming growth factor-beta (TGF-β) in the wound microenvironment always leads to hypertrophic scars (HS) formation by regulating cell fates and crosstalk among various types of cells, such as macrophages and fibroblasts. This study reports that an injectable, self-assembling LA-peptide hydrogel has the potential to facilitate scarless cutaneous wound healing through dynamically adsorbing TGF-β within the wound environment. We found that the released LA peptides led to the suppression of both the PI3K/Akt and TGF-β/Smad2/3 pathways in macrophages and fibroblasts. As expected, the application of LA-peptide hydrogel alleviated the M2 type polarization of macrophages and inhibited fibroblasts activation by adsorbing TGF-β both <i>in vitro</i> and <i>in vivo</i>. Furthermore, designated concentrations of the LA-peptide hydrogel achieved controlled release of LA peptides, enabling dynamic regulation of TGF-β for maintaining microenvironment homeostasis during different phases of wound healing. This contributed to the inhibition of HS formation without delaying wound healing in both a mouse full-thickness skin wound model and a rabbit ear scar model. Overall, the LA-peptide hydrogel provides promising avenues for promoting scarless healing of wounds, exemplifying precision medicine-guided targeting of specific pathogenic molecules, such as TGF-β, and highlighting the significance of dynamic regulation of TGF-β homeostasis in wound microenvironment.