The Development of Cell-Penetrating Peptides for Efficient and Selective In Vivo Expression of mRNA in Spleen Tissue

mRNA-based therapeutics are presently one of the nucleic acid-based therapeutics with a high potential for extraordinary success as preventive vaccines. Current applications with mRNA therapeutics rely on lipid nanoparticle (LNP) mediated delivery of nucleic acids. In order to achieve the transition from preventive to therapeutic vaccines, there is a challenge of delivering the mRNA into non-hepatic tissues, especially into lymphoid tissues such as the spleen and lymph nodes. In this work, we characterize new cell-penetrating peptides NF424 and NF436 that exhibit preferential delivery of mRNA into the spleen after a single i.v. injection, without the use of any active targeting mechanisms. We show that between the spleen, liver, and the lungs, >95% of mRNA expression arises in the spleen tissue and the majority of expression occurs in the dendritic cells. The cell-penetrating peptides NF424 and NF436 represent promising candidates for cancer immunotherapeutic applications with tumor antigens.

Automated summary

mRNA-based therapeutics have great potential as preventive vaccines, but the challenge lies in delivering mRNA to non-hepatic tissues, such as the spleen and lymph nodes, in order to transition from preventive to therapeutic vaccines. This study discovered new cell-penetrating peptides NF424 and NF436 that can selectively deliver mRNA to the spleen without the need for active targeting mechanisms. The majority of mRNA expression occurs in dendritic cells within the spleen, making NF424 and NF436 promising candidates for cancer immunotherapeutic applications with tumor antigens.