Nucleic acid therapy demonstrates great potential in cancer treatment, infectious disease prevention, and vaccine development due to its advantages, such as rapid production, long-lasting effects, and high target specificity. Although nucleic acid therapy is considered ideal for the development of novel therapeutic strategies, its clinical application still faces numerous challenges, including the lack of efficient delivery systems, insufficient drug formulation stability, and the limitations imposed by the skin barrier on drug dosage delivery. Microneedles, as an innovative transdermal drug delivery technology, can penetrate the stratum corneum and directly access the skin's microcirculation, enabling the efficient delivery of genes and drugs. This technology offers several advantages, such as ease of operation, minimally invasive and painless application, and high safety. Combining microneedle technology with nucleic acid therapy fully leverages the strengths of both approaches, significantly enhancing therapeutic efficacy and bioavailability while maximizing treatment potential. This review explores the application prospects and advantages of combining microneedle delivery systems with nucleic acid therapy.