Self‐Assembly of Anti‐Inflammatory Peptide Amphiphiles for Mucosal Health

Broad spectrum anti‐inflammatory peptide amphiphiles (AIF‐PAs) have been developed as an innovative strategy for the treatment of chronic mucosal inflammation and the prevention of HIV transmission. Novel lipopeptides based on two linear sequences of anti‐inflammatory peptides were obtained by solid‐phase peptide chemistry. In a pilot study, ex vivo exposure of colorectal tissue explants from Crohn's disease patients to AIF‐PAs induced a downregulation of the proinflammatory profile. Furthermore, the HIV inhibitory potency of AIF‐PAs was evaluated ex vivo in colorectal tissue explants, obtaining sub‐micromolar IC 50 values. Characterization of AIF‐PAs self‐aggregation in aqueous solution revealed that the net charge distribution within the peptides influenced their conformation in water and their self‐assembly into larger structures. AIF‐PAs with neutral net charge displayed a β‐sheet conformation, whereas AIF‐PAs with positive net charge were characterized by a random coil conformation. The morphology of the nanostructures fully correlated with the peptide secondary structure and self‐aggregation levels. Interactions with model membranes and epithelial cells demonstrated that the cationic charge and amphiphilic nature of self‐assembled AIF‐PAs facilitated their binding and localization to lipid bilayers and cell membranes. Finally, AIF‐PAs were unable to cross epithelial cell monolayers in permeability assays, indicating a low mucosal permeation potential. Their lack of permeation reduces systemic absorption, thus concentrating and retaining the bioactive peptides at the mucosal surface, where local activity is desired. In summary, peptide‐based therapies leverage the beneficial anti‐inflammatory properties of peptides, combined with amphiphilic structures that allow precise targeting and improved delivery to mucosal tissues.