High gene delivery efficiency of alkylated low-molecular-weight polyethylenimine through gemini surfactant-like effect

To our knowledge, the mechanism underlying the high transfection efficiency of alkylated low-molecular-weight polyethylenimine (PEI) is not yet well understood. In this work, we grafted branched PEI (molecular weight of 1,800 Da; bPEI1800) with lauryl chains (C₁₂), and found that bPEI1800-C₁₂ was structurally similar to gemini surfactant and could similarly assemble into micelle-like particles. Stability, cellular uptake, and lysosome escape ability of bPEI1800-C₁₂/DNA polyplexes were all greatly enhanced after C₁₂ grafting. bPEI1800-C₁₂/DNA polyplexes exhibited significantly higher transfection efficiency than Lipofectamine 2000 in the presence of serum. Bioluminescence imaging showed that systemic injection of bPEI1800-C₁₂/DNA polyplexes resulted in intensive luciferase expression in vivo and bioluminescence signals that could be detected even in the head. Altogether, the high transfection efficacy of bPEI1800-C₁₂ was because bPEI1800-C₁₂, being an analog of gemini surfactant, facilitated lysosome escape and induced the coil-globule transition of DNA to assemble into a highly organized micelle-like structure that showed high stability.