Fluorinated Ribonucleocarbohydrate Nanoparticles Allow Ultraefficient mRNA Delivery and Protein Expression in Tumor-Associated Myeloid Cells

Ribonucleic acids (RNA) are commonly formulated into lipid nanoparticles (LNP) for in vivo use, but challenges exist with systemic delivery and low in vivo expression efficiency. Inspired by ribonucleoprotein complexes in cells, we created synthetic ribonucleocarbohydrate (RNC) complexes based on cyclodextrin nanoparticles with ferrocenyl fluorocarbons capable of carrying mRNA and additional small-molecule drug payloads, facilitating lysosomal escape and immune stimulation all in the same nanoparticle. We show that this strategy results in highly efficient myeloid cell targeting (dendritic cells and MHC expressing macrophages) and protein expression following systemic administration. The RNC platform should have broad applications in vaccine development, immunosuppression, and immunostimulation for various diseases.