Serum factors create species-specific barriers to hepatic gene transfer by lipid nanoparticles in liver-humanized mice

, primary human hepatocytes (PHHs) were transfected by LNPs containing lipids SM-102, LP01, or ALC0315 in the presence of normal mouse serum, but not chimeric NSG-PiZ serum. SM-102 LNP transfection of PHH was also inhibited by naive untransplanted NSG-PiZ serum. However, serum from NSG mice supported PHH transfection by SM-102 LNP. These results suggest that inhibitory factors in NSG-PiZ mouse serum are responsible for the lack of human hepatocyte transduction in chimeric mice. Finally, we found that LNPs displaying trivalent N-acetylgalactosamine (TriGalNAc), which targets them to the asialoglycoprotein receptor, can overcome species restriction, transfecting both mouse and human hepatocytes in chimeric NSG-PiZ mice.