Preformulated, Shelf-Stable, Dendritic Cell-Targeting Nanogel mRNA Vaccine Delivery Platform

Abstract

Current mRNA-based vaccine platforms are limited by complex fabrication, stringent cold-chain dependence, and off-target in vivo delivery, restricting their global accessibility and targeting precision. Here we show a modular mRNA delivery platform; our approach integrates inverse microemulsion-derived polymeric nanogels with adsorption-based mRNA loading and the capability for ligand-directed targeting to develop targeted reductively cleavable acrylate-based inverse microemulsion nanogels (TRAINs). By decoupling nanoparticle fabrication from mRNA loading, preformed TRAINs can be stockpiled and later combined with newly designed mRNA, enabling a plug-and-play strategy for rapid adaptation to emerging pathogens, which is particularly advantageous for pandemic preparedness. This architecture supports efficient mRNA association and robust cellular uptake and translation in HEK293T cells. TRAIN also enables postsynthetic surface functionalization; as a proof of concept, CD206-targeted TRAINs promoted selective delivery to antigen-presenting cells (APCs), producing sustained and localized protein expression in BALB/c mice and preferential mRNA delivery to myeloid APCs in heterogeneous human peripheral blood mononuclear cells. Together, these results demonstrate TRAINs as a surface-customizable, adsorption-based mRNA delivery platform with potential for APC-targeted vaccination and rapid, adaptable vaccine deployment.