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

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.