A Novel Surfactant with Short Hydrophobic Head and Long Hydrophilic Tail Generates Vesicles with Unique Structural Feature

Abstract Surfactant molecules typically have a long hydrophobic tail and a short hydrophilic head group. It remains unexplored if surfactants can have a short hydrophobic head group and a long hydrophilic tail. Designing such surfactants is a challenge as a lengthy hydrophilic tail would completely solubilize the molecules. In this context, herein, the Fmoc‐functionalized Gly‐Pro‐Hyp (GPO) tripeptide repeat‐based molecule (Fm‐GPO) with fluorenyl moiety as a short hydrophobic head and peptide as a long hydrophilic tail is demonstrated as a reverse surfactant at physiological pH, for the first time. π–π stacking of the fluorenyl moieties and intermolecular hydrogen bonding between the peptide chains with extended polyproline‐II structure promoted the self‐assembly into spherical vesicles with a unique feature of a large hydrophilic area in the interior and exterior of the bilayer. The current Fm‐GPO system offers a new class of surfactants with unique features that can aid in the design of drug‐loaded vehicles, which can be target‐specific as the peptide chain can be manipulated with different functional ultra‐short peptide sequences.