GalNAc End-Capped Poly(β-amino ester)s with Screened Side Chains for Efficient Gene Delivery

Area of Science:

• Biomaterials Science
• Gene Therapy
• Nanotechnology

Background:

• Plasmids are crucial gene therapy vectors, but efficient delivery is a significant hurdle.
• Poly(β-amino esters) (PBAEs) show promise for non-viral gene delivery but face toxicity and targeting limitations.

Purpose of the Study:

• To design and synthesize a novel PBAE with disulfide bonds and N-acetylgalactosamine (GalNAc) for enhanced plasmid delivery and liver targeting.
• To evaluate the transfection efficiency, toxicity, and therapeutic efficacy of the novel GalNAc-PBAE in a liver fibrosis model.

Main Methods:

• Synthesis of novel GalNAc-terminated PBAEs with disulfide bonds and tertiary amine side chains.
• In vitro transfection efficiency assays and comparison with commercial reagents.
• In vivo studies in a mouse model of acute liver fibrosis using a plasmid encoding HGF.

Main Results:

• Optimized GalNAc-PBAE demonstrated superior transfection efficiency compared to a benchmark PBAE (C28-E7) and Lipo2000.
• GalNAc moieties facilitated efficient liver targeting of plasmid-PBAE polyplexes.
• In vivo administration significantly mitigated liver fibrosis and improved liver function in mice.

Conclusions:

• The novel GalNAc-PBAE is a promising non-viral vector for efficient plasmid delivery and gene therapy, particularly for liver diseases.
• The designed PBAE overcomes limitations of conventional carriers, offering enhanced efficacy and tissue-specific targeting.
• This GalNAc-PBAE holds potential for clinical translation in treating liver fibrosis and other hepatic conditions.