Hybrid Poly(β-amino Ester) and Poly(Amino Alcohol Esters) Polymers for mRNA Delivery

Background/Objectives: While the therapeutic potential of mRNA has attracted considerable attention in recent years, the associated nano systems to aid delivery remain incompletely understood. Delivery vectors are essential in the therapeutic application of mRNA and often consist of lipids, polymers or combinations thereof. High performing polymer families have been identified, and structure-function studies have produced insights on the role of amine groups, end groups and central monomers. This study aims to optimise the polymer backbone structure using polymer systems consisting of dual monomers or a hybrid monomer enabling insights into fine scale structure modifications. Methods: Polymer structures are designed to tune linear or cyclic central groups, hydrolysable ester groups and ionisable amines, which are further optimised with controlled distribution of structural elements. Polymers were synthesised using an amine monomer and either a combination of an acrylate and a glycidyl monomer or a novel monomer combining acrylate and glycidyl functionalities, resulting in hybrid poly(β-amino ester) and poly(amino alcohol esters) polymers (HyPBAAE), the performance of which was evaluated through nanoparticle characterisation and in vitro experiments Results: Good polyplex formation and transfection performance was observed for several polymers and could be linked to properties such as linearity and hydrophobicity. High performance was also achieved with structurally very different polymers exhibiting different physicochemical characteristics. This contrast suggests different manners of interacting with mRNA, depending on the combined properties of a polymer. Conclusions: Overall, the most favourable balance between transfection efficiency and cell viability was observed for two structurally and physiochemically distinct polymers: one consisting of independently combined poly(β-amino ester) and poly(amino alcohol esters) building blocks and another consist-ing of a novel monomer combining poly(β-amino ester) and poly(amino alcohol esters) properties. Showing that different combinations of structural elements and polymer properties can achieve comparable performance, highlighting the interdependence of properties within a nano system.