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Although microRNA (miRNA)\u2010based gene therapy shows promise, its clinical translation is limited by rapid degradation in serum and the barrier function of the stratum corneum. Herein, we engineer a programmable, targeted, and non\u2010invasive nanoplatform, termed MARS (MUC1\u2010Aptamer\u2010functionalized, tetrahedral framework nucleic acid\u2010based miRNA delivery system for gene Silencing). The therapeutic miR\u201030a\u20105p is encapsulated within a self\u2010assembled DNA tetrahedron, an architecture that confers exceptional structural stability. The framework is specifically functionalized with an MUC1 aptamer to act as a navigator for active tumor targeting while simultaneously carrying the gene\u2010silencing payload. In vitro assays demonstrate that MARS successfully delivers miR\u201030a\u20105p into A375 cells, effectively silencing the transcription factor E2F7 and subsequently triggering the intrinsic apoptotic pathway. Importantly, in vivo studies using a xenograft mouse model reveal that topically applied MARS can penetrate the skin barrier and accumulate in tumor tissues, achieving a tumor growth inhibition rate of 66.86%, comparable to intravenous anti\u2010PD\u2010L1 immunotherapy but with superior safety, compliance, and cost\u2010effectiveness. This study presents MARS as a robust strategy that integrates stability, programmable dual\u2010functionality (targeting and gene silencing), and non\u2010invasive transdermal capabilities, providing a promising strategy for localized melanoma treatment.<\/jats:p>","DOI":"10.1002\/smll.74557","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T10:50:31Z","timestamp":1783680631000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Non\u2010Invasive Transdermal Delivery of miR\u201030a\u20105p via MUC1\u2010Aptamer\u2010Guided Tetrahedral DNA Nanostructures for Gene Silencing in Cutaneous Melanoma"],"prefix":"10.1002","volume":"22","author":[{"given":"Zhou","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology Sichuan 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Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9538-7134","authenticated-orcid":false,"given":"Songhang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology Sichuan University  Chengdu Sichuan 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