3D Macrocyclic Structure Boosted Gene Delivery: Multi-Cyclic Poly(β-Amino Ester)s from Step Growth Polymerization

Abstract

The topological structures of polymers play a critical role in determining their gene delivery efficiency. Exploring novel polymeric structures as gene delivery vectors is thus of great interest. In this work, a new generation of multi-cyclic poly(β-amino ester)s (CPAEs) with unique topology structure was synthesized for the first time via step growth polymerization. Through controlling the occurrence stage of cyclization, three types of CPAEs with rings of different sizes and topologies were obtained. In vitro experiments demonstrated that the CPAEs with macro rings (MCPAEs) significantly boosted the transgene expression comparing to their branched counterparts. Moreover, the MCPAE vector with optimized terminal group efficiently delivered the CRISPR plasmid coding both Staphylococcus aureus Cas9 nuclease and dual guide sgRNAs for gene editing therapy.

Recent developments of polymeric delivery systems in gene therapeutics

“…Therefore, further clarification of the relationship between the composition and structure of the vectors and the various stages in the transfection process will help to design high-performance polymer gene vectors. (2) The PDI of polymers is extensive, and polymers with different molecular weights play different roles in the delivery process. Therefore, preparing polymers with narrower molecular weight distributions will help to clarify the relationship between polymer structure and function.…”

“…2d). 2 The other ring shapes and end-group distributions of the individual CPBAEs were verified using fluorescence spectroscopy and 2D-NMR. Macrocyclic PAE (MCPBAE) and its complexes had significantly enhanced DNA condensation, cellular uptake, and DNA protection compared to other CPBAEs and HPBAEs, which promoted the expression of transfected genes.…”

“…Therefore, scientists have further developed various topological structures of polymers, including linear, branched, dendritic, star, and ring structures, to explore the effects of different topologies on gene transfection efficiency. 40,41 Zhao et al exploited a linear oligomer combinatorial branching strategy to create highly branched linear poly…”

“…1 According to Emergency Research's market research, internationally relevant gene therapy companies are expected to generate approximately $6.6 billion in revenue by 2027. 2 The treatment of relevant diseases is achieved by introducing exogenous nucleic acids into target cells, inducing gene silencing (inhibition of pathological protein production), 3 gene expression (promotion of therapeutic protein expression), 4 and gene editing (modification of dysfunctional genes). 5 However, multiple intra- and extracellular barriers must be overcome for effective gene transfection.…”

Sugar alcohol-modified polyester nanoparticles for gene delivery via selective caveolae-mediated endocytosis

“…7 Over the years the polymer structure has been optimized for transfection efficiency and stability in vivo . 8–10 The chemical flexibility of the polymer has been explored for improving its transfection efficiency 7–9,11,12 and overcoming physical barriers for organ- and cellular-level tropism. 13–15 More recently, combinatorial libraries emphasizing the physiochemical diversity of the choice of amines and divinyl monomers have been employed for organ tropism of the liver, spleen, and lungs.…”