Galloyl Dialkyl Lipids Drive Encapsulation of Peptides into Lipid Nanoparticles by Hydrogen Bonding

J Am Chem Soc. 2025 Jan 8;147(1):1307-1318. doi: 10.1021/jacs.4c15688. Epub 2024 Dec 19.

Abstract

The intracellular delivery of peptides and proteins is crucial for various biomedical applications. Lipid nanoparticles (LNPs) have emerged as a promising strategy for delivering peptides to phagocytic cells. However, the diverse physicochemical properties of peptides necessitate tailored formulations. This study introduces a generic approach using galloyl (GA)-functionalized lipids for the encapsulation of peptides in LNPs via hydrogen bonding between the ubiquitously present amides in peptides and the multivalently displayed galloyl phenol groups in GA-LNPs. In vitro studies showed that GA-LNPs significantly improved the cellular uptake of peptides and activated immune responses when combined with Toll-like receptor (TLR) agonists MPLA and IMDQ. In vivo, GA-LNPs accumulated in the spleen and enhanced peptide delivery to antigen-presenting cells. GA-LNPs coencapsulating peptide antigens and TLR agonists elicited robust antigen-specific CD8+ T-cell responses in mice.

MeSH terms

  • Animals
  • Humans
  • Hydrogen Bonding*
  • Lipids* / chemistry
  • Liposomes
  • Mice
  • Nanoparticles* / chemistry
  • Peptides* / chemistry

Substances

  • Peptides
  • Lipids
  • Lipid Nanoparticles
  • Liposomes