Effects of Amino Side Chain Chemistry on Polyaspartamide-Based Polyplexes for mRNA Delivery

Cationic units in synthetic carriers are a key determinant for the efficient intracellular delivery of mRNA, but their systemic evaluation for mRNA translation efficacy in target cells was not fully understood. A series of amphiphilic polyaspartamide derivatives (PAsp(R/CHE)) with various amino ( R ) groups and cyclohexylethylamine (CHE) were synthesized to understand the effects of R groups in polyplex formation and their intracellular delivery efficacies of mRNA, including mRNA binding, intracellular uptake, and endosomal escape. All PAsp(R/CHE)s successfully formed polyplexes with firefly luciferase-coded mRNA (FLuc mRNA), having a hydrodynamic diameter of 90–160 nm with a relatively narrow polydispersity index and positive surface charges. PAsp(R/CHE) polyplexes with R = diethylenetriamine (DET) and 2,2′-diamino- N -methyldiethylamine (MDE) exhibited the highest FLuc mRNA expression …