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Here a novel bioengineered hair germ (BHG) is developed using thermodynamically incompatible mucopolysaccharides to enhance HF regeneration efficiency. Mucopolysaccharide\u2010based hydrogels are synthesized by grafting amino and diethylamino groups (dihydroxyphenylalanine\u2010grafted hyaluronic acid (HME) hydrogels) for rapid gelation and strong wetting adhesion. Dual\u2010layered microspheres are fabricated using a co\u2010flow microfluidic system, with HME as the outer shell and gelatin methacrylate (GelMA) as the core, achieving thermodynamic incompatibility. The Wnt3a protein is encapsulated for sustained release. RNA sequencing, reverse transcription quantitative polymerase chain reaction (RT\u2010qPCR), and functional validation are used to study the molecular mechanisms of HF regeneration. Results show that HME hydrogels exhibit excellent adhesion, shear\u2010thinning behavior, and biocompatibility. The microspheres release Wnt3a for up to 9 days, with high\u2010throughput sequencing revealing upregulation of HF regeneration genes like <jats:italic>Ctnnb1<\/jats:italic> and <jats:italic>Lef1<\/jats:italic>, and activation of the Wnt signaling pathway, while hypoxia\u2010related genes such as <jats:italic>Hif\u20101\u0251<\/jats:italic> are downregulated. Pathway enrichment analyses confirm the enrichment of HF regeneration pathways. In conclusion, the HME\u2010based BHG microspheres effectively promote in vivo HF regeneration, offering a promising solution for hair loss treatment and regeneration.<\/jats:p>","DOI":"10.1002\/advs.202416361","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T12:50:44Z","timestamp":1741697444000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Construction of Large\u2010Scale Bioengineered Hair Germs and In Vivo Transplantation"],"prefix":"10.1002","volume":"12","author":[{"given":"Yangpeng","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Plastic and Aesthetic Surgery Department of Hematology Nanfang Hospital Southern Medical University  Guangzhou Guangdong 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhui","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Plastic and Aesthetic Surgery 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