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.