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 IC50 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.