PEG shedding-rate-dependent blood clearance of PEGylated lipid nanoparticles in mice: Faster PEG shedding attenuates anti-PEG IgM production

•Fast- but not slow-shedding PEG-lipid attenuated anti-PEG IgM production in mice.•Fast- but not slow-shedding PEG-lipid maintained payload siRNA activity.•Fast shedding did not stop rapid LNP clearance caused by pre-existing anti-PEG IgM.•This IgM reduced RNAi activity by uptake shift from hepatocytes to Kupffer cells.