PEG400-mediated nanocarriers improve the delivery and therapeutic efficiency of mRNA tumor vaccines

Dendritic cell (DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor vaccines. The targeting ligands are often modified on nanocarriers by polyethylene glycol (PEG) linker in mRNA delivery systems. Whether the PEG linker length influences the targeting delivery efficiency of mRNA nanocarrier in vivo remains unclear. Here, we designed and constructed DC-targeted mRNA delivery systems modified by mannose via different PEG linker lengths (100/400/1000/2000) (MPn-LPX). The top candidate MP400-LPX (the linker was PEG400) showed the optimal mRNA expression and antigen presentation owing to the highly efficient uptake by DCs. Furthermore, MP400-LPX could better inhibited tumor growth and extended survival in the E.G7-OVA lymphoma and TC-1 cervical tumor mouse model. Collectively, these results demonstrated that PEG400 was the optimal linker for the PEGylated DC-targeted mRNA vaccines. Our findings provided a new platform for the rational design of targeted mRNA nanovaccines with shorter-length PEG.