Nonviral polycation-based gene carriers (polyplexes) have attracted attention as safe and efficient gene delivery systems. Polyplex micelles comprised of poly(ethyleneglycol)-block-poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-PAsp(DET)) and plasmid DNA (pDNA) have shown high transfection efficiency with low toxicity due to the pH-sensitive protonation behavior of PAsp(DET), which enhances endosomal escape, and their self-catalytic degradability under physiological conditions, which reduces cumulative toxicity during transfection. In this study, we improved the safety and transfection efficiency of this polyplex micelle system by adding an anionic polycarbohydrate, chondroitin sulfate (CS). A quantitative assay for cell membrane integrity using image analysis software showed that the addition of CS markedly reduced membrane damage caused by free polycations in the micelle solution. It also reduced tissue damage and subsequent inflammatory responses in the skeletal muscle and lungs of mice following in vivo gene delivery with the polyplex micelles. Subsequently, this led to prolonged transgene expression in the target organs. This combination of polyplex micelles and CS holds great promise for safe and efficient gene introduction in clinical settings.
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