Fluorination as a Molecular Design Parameter for Programming Peptide Nanocarriers

ABSTRACT

Peptide‐based nanocarriers offer unique opportunities for programmable self‐assembly (SA), yet rational design strategies that couple structural control with biological function remain limited. In particular, fluoropeptides have been largely inaccessible as modular building blocks until the recent availability of enantiomerically pure fluorinated amino acids (FAAs) in gram‐scale quantities, preventing their systematic use in functional nanomaterials. Here, we introduce fluorination as a quantitative molecular design parameter to program peptide SA, morphology, and biological performance. A homologous series of amphiphilic fluoropeptide–RGD conjugates was constructed in which the degree of side‐chain fluorination is precisely controlled. We show that fluorination does not monotonically enhance assembly, but instead defines a narrow design window in which compact, non‐amyloid fibrillar architectures emerge. Mechanistic insight from molecular dynamics (MD) simulations reveals how fluorine‐induced modulation of hydrophobic interactions and hydration disrupts classical β‐sheet packing. The optimized trifluorinated conjugate exhibits high drug‐loading capacity, pH‐triggered release, receptor‐specific cellular uptake, and low cytotoxicity, while remaining enzymatically degradable. Together, these results establish fluorinated peptide segments as a previously inaccessible and programmable handle for the rational design of peptide‐based nanocarriers.