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However, current therapies lack precise and controllable layer\u2010specific intervention. Here, we present a threaded microneedle\u2010mRNA platform enabling stratified, targeted delivery. Guided by spatial transcriptomics and clinical validation, we identified layer\u2010specific targets in skin fibrosis. Optimized lipid nanoparticles (LNPs) were integrated into a microneedle design featuring a fast\u2010releasing superficial hydrogel that delivers a SIRT1 agonist to mitigate dermal fibroblast senescence, and helical grooves that directionally deposit PGC1\u03b1 mRNA\u2013LNPs into subcutaneous adipose during rotational insertion for in situ expression and reversal of adipocyte fibrotic phenotypes. In bleomycin\u2010induced murine fibrosis, the system reduced dermal senescence and ECM deposition, restored subcutaneous adipose architecture, and attenuated overall fibrosis. This layer\u2010specific microneedle\u2013mRNA strategy offers a precise therapeutic pathway for complex skin diseases.<\/jats:p>","DOI":"10.1002\/advs.77624","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:37:53Z","timestamp":1789979873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Layer\u2010Specific Dermal and Subcutaneous Delivery via Modular LNP\u2013Hydrogel\u2010Integrated Threaded Microneedles"],"prefix":"10.1002","author":[{"given":"Fangzhou","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Plastic &amp; Reconstructive Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai People's Republic of China"},{"name":"Department of Plastic Surgery, State Key Laboratory of Trauma, Burns and Combined Injury Southwest Hospital, Third Military Medical University (Army Medical University)  Chongqing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3194-3373","authenticated-orcid":false,"given":"Yixiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Plastic &amp; 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