Hepatitis B (HB) is a viral infectious disease that seriously endangers human health, and since there are no radical drugs to counter this, effective and safe therapies urgently need to be developed. HB virus (HBV) mainly infects hepatocytes (HCs), while the drugs are easily phagocytosed by Kupffer cells (KCs). In this study, the glutathione concentration difference between HCs and KCs was examined and utilized in an ideal drug-release strategy. Here, galactosylated chitosan-oligosaccharide-SS-octadecylamine (Gal-CSSO) was prepared to accurately deliver 10-23 DNAzyme DrzBC (blocking HBeAg expression) or DrzBS (blocking HBsAg expression) in targeted HB therapy. Gal-CSSO systems exhibited low cytotoxicity, endosomal escape, and glutathione responsiveness. The HBeAg and HBsAg secretion of HepG2.2.15 was significantly decreased by Gal-CSSO systems, and the maximum inhibition rates were 1.82-fold and 2.38-fold greater than those of commercial Lipofectamine 2000 (Lipo2000) systems. Gal-CSSO systems exhibited HC targeting and HC microenvironmental responsiveness without noticeable hepatotoxicity or systemic toxicity. The HBeAg and HBsAg titers of the HBV-infected mice were evidently decreased by Gal-CSSO systems, and the inhibition rates were 1.52-fold and 1.22-fold greater than those of Lipo2000 systems. This study presents a kind of glycolipid-like polymer micelles that promise efficient and safe gene therapy of HB.
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