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Here, a microbial polysaccharide\u2010based in situ self\u2010gelling 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\u2010adhesive hydrogel with excellent biocompatibility. In mouse deep second\u2010degree 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\u2010capture assays identify CD14 as a specific binding receptor for HD. Mechanistically, CD14 engagement by HD reprograms macrophage responses, suppressing nuclear factor\u2010\u03baB (NF\u2010\u03baB) signaling and altering the macrophage\u2010derived 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\u2010targeting function of a microbial polysaccharide and establish an in situ self\u2010gelling immunomodulatory platform that actively reprograms the wound microenvironment to enable high\u2010quality skin regeneration.<\/jats:p>","DOI":"10.1002\/advs.77602","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:21:14Z","timestamp":1788754874000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A CD14\u2010Targeting In Situ Hydrogel Directs Macrophage Reprogramming to Minimize Scar Formation"],"prefix":"10.1002","author":[{"given":"Rui","family":"Fang","sequence":"first","affiliation":[{"name":"Center for Molecular Metabolism Nanjing University of Science &amp; Technology  Nanjing People's Republic of China"},{"name":"Key Laboratory of Metabolic Engineering and Biosynthesis Technology Ministry of Industry and Information Technology  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Molecular Metabolism Nanjing University of Science &amp; 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