Combinatorial synthesis of novel polycations for mRNA delivery via Ugi 4-component polymerisation.

RNA therapeutics offer solutions to treat previously undruggable diseases, but successful RNA delivery requires efficient and safe vectors. Cationic polymers provide one technology platform for this delivery, however, despite many current materials in this class showing promise when tested in cells, none have yet progressed to the clinic. Existing commercially available polymers evaluated for RNA delivery have either limited structural variety or poorly addressable functionality, which means that tuning of pharmaceutical properties is difficult. In order to control better some parameters of key importance for RNA delivery, such as assembly with nucleic acids, internalisation into target cells and degradation after payload release, new chemistries and structures are needed. Multicomponent polymerisations provide a means to access easily highly functionalised materials, thus here we report the use of Ugi 4-component polymerisation to synthesise a range of cationic polyamides. We demonstrate a facile synthetic route to a diverse polymer library which, when screened for in vitro transfection with mRNA, showed several polymer structures with high potency in selected cell lines.