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

PEGylation-modification with polyethylene glycol (PEG)-is useful for stabilizing lipid nanoparticles (LNPs). However, such PEGylation can prevent small interfering RNA (siRNA) encapsulated in LNPs from exerting its gene-silencing effects by disrupting the interaction of LNPs with target cells and by inducing the accelerated blood clearance phenomenon via anti-PEG IgM. PEG-lipids with short acyl chains can be used to address these issues because they are quickly shed from LNPs after administration; however, there are few reports on the relationships among PEG shedding rate, anti-PEG IgM production, and the gene-silencing activity of siRNA upon repeated LNP administration. Here, in mice, we found that LNPs conjugated to a fast-shedding PEG-lipid (short acyl chain) induced less anti-PEG IgM compared with LNPs conjugated to a slow-shedding PEG-lipid (long acyl chain). Moreover, pretreatment of mice with LNPs conjugated to the slow-shedding PEG-lipid caused loss of RNA interference activity after subsequent LNP administration because the payload siRNA was delivered primarily to Kupffer cells rather than to hepatocytes. Together, these findings imply that manipulating PEG shedding rate and anti-PEG antibody production is enormously important in the development of RNA interference-based therapeutics utilizing LNP technology.

• Publication year

  2020

• Venue

  International journal of pharmaceutics

• Publication date

  2020-08-19

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.ijpharm.2020.119792PMID 32827675
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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