Poly (β‐amino ester)s (PAEs): from structure design to gene delivery application

Poly(β-amino ester) (PAE) has emerged as a key non-viral gene delivery vector, with great potential for clinical applications after two decades of development. Despite extensive efforts to optimize its structure by screening chemical composition, molecular weight (MW), terminal groups, and topology, the DNA delivery efficiency of PAE still lags behind that of viral vectors. The aim of this dissertation is to explore the structural properties of PAE further and identify ways to improve its delivery efficiency. Chapter 1 gives a general introduction to the development history of PAE as gene delivery vector and discusses the latest designs and developments for the improved gene delivery. Chapter 2 investigates the effect of polymer structure on gene delivery performance from a new perspective - polymer components and their distribution (PCD). The study reveals the individual properties of different polymer components and their synergistic effects on gene delivery performance. By optimizing the PCD, a series of high-efficiency polymer vectors that surpass current commercial reagents, such as jetPEI and Lipo3000, were successfully developed. Chapter 3 explores the branch unit distribution (BUD) of highly branched PAE (HPAE) for the first time. The study reveals that HPAEs prepared from different reaction concentrations have varying BUDs. The research highlights the essential role of BUD in HPAE transfection capability and shows that HPAEs with a more uniform distribution of branch units exhibit better transfection efficacy. Chapter 4 introduces a new generation of PAE with a novel multi-cyclic topology. Three types of CPAEs with rings of different sizes and topologies were obtained by controlling the occurrence stage of cyclization. In vitro experiments demonstrate that the CPAEs with macro rings (MCPAEs) significantly enhance transgene expression compared to their branched counterparts. Chapter 5 summarises the entire project and discusses some possible research directions for future investigations.