Elevating nucleic acid delivery via a stable anionic peptide-dextran ternary system

Nucleic acid-based therapies hold promise for treating previously intractable diseases but require effective delivery vectors to protect the therapeutic agents and ensure efficient transfection. Cationic polymeric vectors are particularly notable for their adaptability, high transfection efficiency, and low cost, but their positive charge often attracts blood proteins, causing aggregation and reduced transfection efficiency. Addressing this, we designed an anionic peptide-grafted dextran (Dex-LipE5H) to serve as a cross-linkable coating to bolster the stability of cationic polymer/nucleic acid complexes. The Dex-LipE5H was synthesized through a Michael addition reaction, combining an anionic peptide (LipE5H) with dextran modified by divinyl sulfone. We demonstrated Dex-lipE5H utility in a novel ternary nucleic acid delivery system, CDex-LipE5H/PEI/nucleic acid. CDex-LipE5H/PEI/nucleic acid demonstrated lower cytotoxicity and superior anti-protein absorption ability compared to PEI/pDNA and Dex-LipE5H/PEI/pDNA. Most notably, the crosslinked CDex-LipE5H/PEI/pDNA demonstrated remarkable transfection performance in HepG2 cells, which poses significant transfection challenges, even in a medium with 20% serum. This system’s effective siRNA interference performance was further validated through a PCSK9 gene knockdown assay. This investigation provides novel insights and contributes to the design of cost-effective, next-generation nucleic acid delivery systems with enhanced blood stability and transfection efficiency.