Transdermal Delivery of an mRNA‐Liposome Vaccine via Dissolving Microneedle to Preserve Vaccine Activity and Enhance Immune Activation

ABSTRACT Although mRNA vaccines have revolutionized modern vaccinology, significant challenges persist owing to their dependence on ultra‐cold storage, patient discomfort, and logistical complications associated with intramuscular (IM) injections. Dissolving microneedles (DMNs) are a promising alternative by enabling minimally invasive transdermal administration that directly engages skin‐resident immune cells, while their fabrication compromises fragile mRNA. Moreover, previous studies have emphasized antibody‐mediated immunity rather than exploiting their capacity for strong T cell responses. In this study, we developed an mRNA‐liposome vaccine via DMN (ML‐DMN) to preserve the mRNA activity in DMN formulations and boost immune cell activation. Incorporating excipients into the formulation retained the mRNA integrity during fabrication, as demonstrated by in vitro luciferase assays. In vivo administration of ovalbumin (OVA) mRNA via ML‐DMN promoted rapid migration and activation of antigen‐presenting cells (APCs) in draining lymph nodes (dLNs) within 24 h, initiating an innate immune response. This led to robust OVA‐specific T cell activation, proliferation, and secretion of key cytokines, confirming a potent adaptive immune response with lower mRNA doses than IM injections. These results suggest that ML‐DMN systems have significant potential to overcome current mRNA vaccine limitations by improving mRNA integration and immune cell targeting, offering a viable strategy for future vaccine development.