Improving gene transfection efficiency of highly branched poly(β-amino ester)s through the in-situ conversion of inactive terminal groups

Abstract

Highly branched poly(β-amino ester)s (HPAEs) have emerged as a safe and efficient type of non-viral gene delivery vectors. However, the presence of inactive terminal secondary amine groups compromises their gene transfection capability. In this study, HPAEs with similar topological structures and chemical compositions but varying numbers of terminal secondary 4-amino-1-butanol (S4) and secondary/tertiary 3-morpholinopropylamine (MPA) groups were synthesized. The results demonstrate that an increased number of secondary/tertiary MPA groups in-situ significantly enhances the DNA binding capability of HPAEs, leading to the formation of smaller HPAE/DNA polyplexes with higher zeta potential, ultimately resulting in superior gene transfection efficiency in bladder epithelial cells. This study establishes a simple yet effective strategy to maximize the gene transfection potency of HPAEs by converting the inactive terminal groups in-situ without the need for complex modifications to their topological structure and chemical composition.