Rapidly separable bubble microneedle-patch system present superior transdermal mRNA delivery efficiency

Traditional mRNA vaccine formulation loaded by lipid nanoparticle (mRNA-LNP) has several shortcomings in clinical application, including the need for cryopreservation, discomfort associated with intramuscular injections, and the risk of liver aggregation. Dissolvable microneedles (DMNs), as a novel transdermal drug delivery platform, can overcome the skin barrier to deliver drugs directly into the skin in a minimally invasive manner. However, mRNA-LNP is unstable and easily degraded during the solidification of DMN. In this study, we proposed to establish a rapidly dissolvable bubble microneedle patch (bMNP) system for the transdermal delivery of mRNA-LNP. We explored to use polyvinyl alcohol (PVA) and trehalose for the first time as matrix material for preparing microneedles. Our results demonstrate that the stability of the mRNA-LNP was obviously improved. The mRNA in this bMNP system can be stored at room temperature for at least one month. Furthermore, the existence of air bubbles between the needle tip and the dorsal scale of bMNP can achieve dorsal scale separation by applying shear force after inserting into subcutaneous tissue, and effectively target lymph nodes in vivo after releasing mRNA-LNP. Using mRNA that encodes the spike protein from SARS-CoV-2 as a test case, the rapidly separable bMNP system induced the production of significant levels of spike-specific IgG antibodies, neutralizing antibodies, and a Th1-polarized T cell response, providing an alternative route for mRNA delivery. Our research is expected to provide a promising transdermal drug delivery strategy that can improve mRNA vaccine accessibility.