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

Xinlong Liu,Yimeng Li,Xinhua Liu,Yangyang Huang,Fujun Wang,Jiafeng Li,Yuqi Guo,Xinyuan Zhu,Lijuan Zhu,Chuan Zhang

Plasmids are widely used gene vectors in gene therapy, yet their efficient delivery remains a major challenge for achieving optimal therapeutic outcomes. Recently, poly(β-amino esters) (PBAEs) have emerged as promising carriers for non-viral gene delivery due to their tunable structures and high delivery efficiency. Nonetheless, the cationic nature of PBAEs raises toxicity concerns, and their lack of tissue-specific targeting capability limits their clinical application. Herein, a novel PBAE for efficient plasmid delivery is constructed, which contains disulfide bonds in the backbone and N-acetylgalactosamine (GalNAc) moieties at the terminals (GalNAc-PBAEs). To address the potential reduction in nucleic acid condensing capacity caused by end-capping PBAE with GalNAc, the commonly used end-capping amines in conventional PBAE are employed as monomers to create GalNAc-PBAEs with tertiary amine side chains. Through side-chain screening, the optimized GalNAc-PBAE exhibits enhanced transfection efficiency, surpassing that of the conventional top-performing PBAE, C28-E7, and rivaling the commercial transfection reagent Lipo2000. Importantly, the GalNAc moieties enable the plasmid-PBAE polyplex to efficiently target the liver. In a mouse model with acute liver fibrosis, the efficient delivery and expression of a representative plasmid encoding HGF significantly mitigate liver fibrosis and improve liver function, demonstrating the potential of the designed PBAE in gene therapy.