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Affecting over 310 million patients worldwide, while effective strategies to halt progression remain lacking. The TGF\u2010\u03b2\u2013mediated fibrotic cascade is the central driver of HS, and siRNA\u2010based therapeutics offer a promising gene\u2010level intervention owing to their high sequence specificity and low off\u2010target risk. However, siRNA translation is limited by rapid degradation, poor transfection, insufficient targeting, and the dense scar barrier that restricts noninvasive delivery. Proteomic analysis revealed that hypertrophic scar fibroblasts (HSFs) exhibit enhanced bioadhesion and protein\u2010binding functions, with Thy\u20101 membrane glycoprotein highly and specifically expressed, providing a target for HSFs\u2010active delivery. We hybridized HSFs membranes with cationic transfersomes using ultrasonic co\u2010extrusion and achieved efficient loading of TGF\u2010\u03b21 siRNA through electrostatic self\u2010assembly. This membrane\u2010hybridized platform enabled multipathway transdermal delivery of siRNA via intercellular transport, transcytosis, and skin appendageal routes, while improving transfection, immune evasion, and homotypic targeting. Studies demonstrated efficient silencing of TGF\u2010\u03b21, suppression of \u03b1\u2010SMA, ECM deposition, and pro\u2010inflammatory cytokine release, thereby mitigating fibrotic progression. The system provides an innovative strategy for transdermal targeted siRNA therapy of HS and other skin diseases requiring genetic intervention.<\/jats:p>","DOI":"10.1002\/advs.77975","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted\u2010Penetrating Biomimetic Hybrid Transfersomes for Enhanced Transdermal Gene Transfection in Hypertrophic Scar Therapy"],"prefix":"10.1002","author":[{"given":"Hui","family":"Xing","sequence":"first","affiliation":[{"name":"Department of Burn and Plastic Surgery Guangzhou Red Cross Hospital Jinan University  Guangzhou China"},{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Biomedical Engineering Jinan University  Guangzhou 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