Powder-attached microneedles for the stable and effective transdermal delivery of clinically validated mRNA-LNP...

Microneedle-based delivery offers a promising strategy for administering mRNA-lipid nanoparticle (mRNA-LNP) vaccines via the skin; however, maintaining mRNA-LNP integrity and achieving effective immune responses remain challenging. This study presents a clinically relevant microneedle platform for the transdermal delivery of clinically validated mRNA-LNP vaccines using powder-attached microneedles (P-MAP) and coated microneedles (C-MAP). The mRNA-LNP vaccine, based on the formulation of Moderna's clinically approved product, was prepared without alteration in their composition or manufacturing method. Lyophilization with stabilizers enabled the production of structurally preserved mRNA-LNP powders, which were physically attached onto the adhesive silicone surface of solid microneedles. To evaluate delivery efficiency and quality, three key parameters were assessed: delivery efficiency (D), mRNA-LNP integrity (I), and release kinetics (R). Integrity (I) showed a strong correlation with humoral immune responses and in vivo protective efficacy. P-MAP exhibited a high I value along with rapid mRNA-LNP release, leading to efficient immune activation, complete protection, and efficient viral clearance in mice, whereas C-MAP, despite achieving comparable delivery efficiency, showed reduced structural integrity and slow-release kinetics, resulting in diminished immune responses and no protective effect. The lyophilized powder formulation also retained mRNA-LNP potency for over six months at 4 °C, demonstrating superior storage stability compared to conventional liquid formulations. Furthermore, this system significantly reduced off-target biodistribution to the liver, indicating a favorable safety profile. These findings emphasize the need to optimize formulation stability and release kinetics for microneedle-based mRNA vaccine platforms. P-MAP provides a stable and clinically relevant strategy for safe and effective delivery of mRNA-LNP vaccine.