Recent advances in nucleotide-based cancer vaccines highlight their promise in cancer immunotherapy, emphasizing the need for efficient delivery systems. Hyaluronic acid (HA) is an attractive carrier for skin cancer treatment due to its biocompatibility and affinity for CD44 receptors overexpressed in tumor cells. In this study, therapeutic mRNA was loaded into HA-based cationic solid lipid nanoparticles (CSLN) to achieve targeted cellular uptake via CD44-mediated pathways. To further enhance transdermal delivery, the mRNA-loaded HA-CSLN were incorporated into a dissolving microneedle system, enabling localized intradermal administration and overcoming the skin barrier. This platform improved mRNA delivery efficiency while minimizing systemic exposure. The HA-CSLN-loaded microneedles exhibited effective antitumor activity and tumor growth suppression, demonstrating their potential as a minimally invasive and targeted mRNA-based immunotherapeutic strategy for skin cancer.