Modular supramolecular polycations enable efficient delivery of RNA therapeutics and vaccines

We describe a modular, diverse and customisable supramolecular-materials platform which can deliver nucleic acids in vitro and in vivo with reduced immunogenicity and enhanced stability compared to lipid analogues. The chemistries deployed enable the generation of multiple host-guest polycationic structures which can associate with RNA to form polyelectrolyte complexes, but which have the unique feature of reversible cross-links, via host-guest interactions of monomers that display aromatic amino acid termini with cucurbit[8]uril (CB[8]). Families of supramolecular polymers can be prepared by simple variation in monomer structure, enabling the tuning of polyelectrolyte complex stability. We demonstrate that these supramolecular polymers and the resultant polyelectrolyte complexes with RNA can be prepared easily via automatable procedures to generate nanoparticles which fully meet Critical Quality Attributes appropriate for manufactured clinical RNA vaccines and therapeutics. We show that these materials deliver RNA to a range of cell types in 2D and 3D culture, displaying reporter-protein expression at levels equivalent to, or greater than, commercial transfection reagents, and with no adverse phenotypic effects in vitro or in vivo . Finally, we provide diverse evidence for the success of the materials platform across a range of nucleic acid types, with expression of mRNA deep within tumours of an orthotopic Triple-Negative Breast Cancer mouse model, knockdown of a kinase implicated in cancer progression via siRNA and of effective protection by factors of up to1000-fold in terms of reduced viral load in an H1N1 influenza virus challenge model in mice following injections of self-amplifying RNA.