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Construction of ROS-Responsive Poly(β-amino ester)-poly(β-thioether ester) Copolymer for Enhancing Gene Delivery and
Qianru Li1,2, Yuhe Zhu1, Jiahui Ding1
1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Biomacromolecules
|September 4, 2025
Summary
Researchers developed a new gene vector, poly(β-amino ester)-poly(β-thioether ester) copolymer (PBAE-TE), to improve gene therapy. This novel vector enhances transfection efficiency and effectively inhibits cancer cell proliferation in vitro and in vivo.
Area of Science:
- Biomaterials Science
- Gene Therapy
- Polymer Chemistry
Background:
- Gene therapy efficacy is often limited by the performance of gene vectors.
- Intracellular reactive oxygen species can negatively impact gene delivery.
- Poly(β-amino ester) (PBAE) is a known nonviral gene vector with potential for improvement.
Purpose of the Study:
- To synthesize and characterize a novel copolymer, PBAE-poly(β-thioether ester) (PBAE-TE), to overcome limitations of traditional PBAE vectors.
- To evaluate the transfection efficiency and cellular uptake of the new PBAE-TE copolymer.
- To assess the gene editing and cancer cell proliferation inhibition capabilities of PBAE-TE based polyplexes.
Main Methods:
- Synthesis of PBAE-TE copolymers by introducing thioether bonds into PBAE.
- Optimization of copolymer composition (monomer feeding ratio and reaction time) to identify the best performing variant (PBAE-TE2-5).
- In vitro transfection assays in various cell lines (SiHa, HeLa, Me180, C666-1, HEK 293T) and 3D spheroid models.
- In vitro and in vivo evaluation of cancer cell proliferation inhibition using PBAE-TE2-5 complexed with CRISPR/Cas9 plasmid.
Main Results:
- The optimized PBAE-TE2-5 copolymer exhibited high transfection efficiencies in SiHa (75.00%) and HeLa (78.70%) cells.
- PBAE-TE2-5 demonstrated superior transfection performance across multiple cell lines compared to unmodified PBAE.
- Enhanced penetration capability was observed in 3D spheroid models, and effective gene editing and cancer cell proliferation inhibition were achieved.
- CRISPR/Cas9 plasmid polyplexes with PBAE-TE2-5 successfully edited target genes (MUC2, HPV16 E7) and inhibited cancer cell growth.
Conclusions:
- PBAE-TE copolymers represent a promising advancement in nonviral gene delivery systems.
- The introduction of thioether bonds enhances vector performance by potentially mitigating reactive oxygen species effects.
- PBAE-TE shows significant potential for effective gene editing and cancer therapy applications.
