Nucleic acids, such as RNA, have shown promise for vaccination applications.Protection of the RNA from nucleases is one of the major concerns for RNA vaccines.We reasoned that charge-dense polyamines might provide optimal protection from nucleases in the body while allowing for functional release in the cytoplasm.Charge-dense polymers such as polyamines based on poly(amido amine) or poly(propylenimine), can condense nucleic acids through interaction with the phosphate backbone, resulting in compact nanoparticles that provide a measure of protection against nucleases.Furthermore, these materials often contain an abundant amount of amines with pKa values between 5 and 7, which have been observed to facilitate release of endocytosed nucleic acid into the cytoplasm through "proton sponge" effect.Polymers, however, can be polydisperse and lack the unimol. identity of small mols.This heterogeneity can impact reproducibility between batches, leading to a greater need for post-production purification, material losses and characterization challenges.Ultimately, these limitations can neg. impact downstream clin. translation.To address these challenges, we have combined the benefits of small mols. with larger polymers to create chem.-defined modified dendrimers that are specifically designed for RNA vaccination.We have shown that the use of these chem.-defined, non-polymeric modified dendrimer mols. instead of more polydisperse amine polymers allow for better definition of the nanoparticulate composition following self-assembly, improving reproducibility.Moreover, the surface chem. of the modified dendrimer nanoparticles enhances the delivery of nucleic acid to target locations.These materials have been used to deliver antigen-expressing self-replicating RNA in vivo, resulting in antibody production and antigen-specific CD8+ T cell responses against the encoded protein antigen.Vaccinated animals gain protective immunity and survive lethal challenges against pathogens such as Ebola virus, H1N1 influenza, Venezuelan equine encephalitis, HPV-induced cancer and the parasite Toxoplasma gondii.