Degradable Terpolymers with Alkyl Side Chains Demonstrate Enhanced Gene Delivery Potency and Nanoparticle Stability

Non-viral gene delivery vectors are attractive due to their potential safety and ease of manufacture, but low transfection potency and poor formulation stability have limited their application. Among the numerous materials that have been studied for gene delivery, poly(β-amino ester)s (PBAEs) represent one promising class of degradable delivery materials. Here, we develop PBAE terpolymers incorporating hydrophobic alkyl side chains that exhibit significantly enhanced transfection potency and resistance to aggregation. Top-performing PBAE terpolymers demonstrated significantly higher transfection potencies in HeLa cells than the commercial reagent, Lipofectamine 2000. Inclusion of alkyl side chains promoted the stability of polymer-DNA complexes under physiological conditions. Furthermore, at high DNA concentrations, PBAE terpolymers with alkyl side chains, but not PBAEs lacking them, could support functionalization with PEG-lipid conjugates to yield particles that maintained their size and transfection activity after incubation at high ionic strength for several hours. The marked improvements in nanoparticle transfection potency and stability offered by these degradable PBAE terpolymers may facilitate the in vivo translation of these materials.