A CD14‐Targeting In Situ Hydrogel Directs Macrophage Reprogramming to Minimize Scar Formation

Despite the urgent need for therapies that enable high-quality skin regeneration with minimal scar formation, current wound dressings remain largely passive and provide limited control over the inflammatory and fibrotic processes that determine repair outcomes. Here, a microbial polysaccharide-based in situ self-gelling powder, Hemoadhican (HD), is shown to actively reprogram the wound microenvironment by targeting macrophage CD14. Upon contact with wound exudate or blood, HD rapidly forms a stable, tissue-adhesive hydrogel with excellent biocompatibility. In mouse deep second-degree burn, rabbit ear hypertrophic scar, and rat abdominal incision models, HD significantly accelerates wound closure, promotes organized collagen remodeling, reduces scar formation, and enhances the regeneration of hair follicles, blood vessels, and neural structures. Protein affinity-capture assays identify CD14 as a specific binding receptor for HD. Mechanistically, CD14 engagement by HD reprograms macrophage responses, suppressing nuclear factor-κB (NF-κB) signaling and altering the macrophage-derived paracrine microenvironment, which subsequently enhances endothelial protein kinase B (AKT) phosphorylation and reduces fibroblast SMAD family member 2 (Smad2) phosphorylation to coordinate angiogenesis and fibrotic remodeling. These findings reveal a previously unrecognized CD14-targeting function of a microbial polysaccharide and establish an in situ self-gelling immunomodulatory platform that actively reprograms the wound microenvironment to enable high-quality skin regeneration.