A Dual-Fusogenic Virus-like Vector Enables Direct Cytosolic Delivery of mRNA Vaccines to Dendritic Cells.

Messenger RNA (mRNA) vaccines hold significant potential for disease prevention and treatment; however, their effectiveness is limited by the inefficiency of current carriers in targeting dendritic cells (DCs) and facilitating endosomal escape to deliver mRNA into the cytosol. In this study, we develop a dual-fusogenic virus-like particle (VLP) cofunctionalized with a DC-targeting fusogen (DC-F) and an endosomal fusogen (E-F), termed DC/E-FVLP. We show that mRNA-loaded DC/E-FVLPmRNA selectively targets DCs and promotes fusion with both the plasma and endosomal membranes, achieving a 28.2% mRNA cytosolic delivery efficiency, which is approximately 60 times greater than that of lipid nanoparticles (LNP). Subcutaneous injection of DC/E-FVLPmRNA markedly enhances mRNA delivery to DCs in lymph nodes, resulting in improved antigen expression and presentation. At a dose of 50 ng mRNA per mouse, DC/E-FVLPmRNA efficiently induces both cellular and humoral immune responses against SARS-CoV-2 antigens and solid tumors. Thus, DC/E-FVLPmRNA holds promise as a potent mRNA vaccine delivery vehicle.