Non‐Invasive Transdermal Delivery of miR‐30a‐5p via MUC1‐Aptamer‐Guided Tetrahedral DNA Nanostructures for Gene Silencing in Cutaneous Melanoma

Cutaneous malignant melanoma is a highly aggressive skin cancer with poor prognosis. Although microRNA (miRNA)‐based 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‐invasive nanoplatform, termed MARS (MUC1‐Aptamer‐functionalized, tetrahedral framework nucleic acid‐based miRNA delivery system for gene Silencing). The therapeutic miR‐30a‐5p is encapsulated within a self‐assembled 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‐silencing payload. In vitro assays demonstrate that MARS successfully delivers miR‐30a‐5p 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‐PD‐L1 immunotherapy but with superior safety, compliance, and cost‐effectiveness. This study presents MARS as a robust strategy that integrates stability, programmable dual‐functionality (targeting and gene silencing), and non‐invasive transdermal capabilities, providing a promising strategy for localized melanoma treatment.