Jet injection potentiates naked mRNA SARS-CoV-2 vaccine in mice and non-human primates by adding physical stress to the skin

Naked mRNA-based vaccines may reduce the reactogenicity associated with delivery carriers, but their effectiveness has been suboptimal against infectious diseases. Herein, we aimed to enhance their efficacy by using a pyro-drive liquid jet injector that precisely controls pressure to widely disperse mRNA solution in the skin. The jet injection boosted naked mRNA delivery efficiency in the mouse skin. Mechanistic analyses indicate that dendritic cells, upon uptake of antigen mRNA in the skin, migrate to the draining lymph nodes for antigen presentation. Additionally, the jet injector activated innate immune responses in the skin, presumably by inducing physical stress, thus serving as a physical adjuvant. From a safety perspective, our approach, utilizing naked mRNA, restricted mRNA distribution solely to the injection site, preventing systemic pro-inflammatory reactions following vaccination. Ultimately, the jet injection of naked mRNA encoding SARS-CoV-2 spike protein elicited robust humoral and cellular immunity, providing protection against SARS-CoV-2 infection in mice. Furthermore, our approach induced plasma activity of neutralizing SARS-CoV-2 in non-human primates, comparable to that observed in mice, with no detectable systemic reactogenicity. ### Competing Interest Statement Competing Interest Statement: Sa.A., M.M., H.A., K.K., and S.U. have filed a patent application related to this study, and NANO MRNA Co., Ltd. (M.M., Sh.A.) holds a right to the patent. K.K. is a founder and a member of the Board of NANO MRNA Co., Ltd. M.M. is an employee of NANO MRNA Co., Ltd. Sh.A. is a CEO and CSO of NANO MRNA Co., Ltd.