Fluorination as a Molecular Design Parameter for Programming Peptide Nanocarriers

Area of Science:

• Biomaterials Science
• Nanotechnology
• Organic Chemistry

Background:

• Peptide-based nanocarriers are promising for drug delivery but lack rational design strategies.
• Fluoropeptides were previously difficult to synthesize, limiting their use in nanomaterials.

Purpose of the Study:

• To introduce fluorination as a quantitative parameter for designing peptide self-assembly (SA).
• To explore the impact of controlled fluorination on peptide nanocarrier morphology and biological function.

Main Methods:

• Synthesized a homologous series of amphiphilic fluoropeptide-RGD conjugates with controlled fluorination.
• Utilized molecular dynamics (MD) simulations to understand the mechanism of fluorination on peptide assembly.
• Evaluated nanocarrier properties including drug loading, release kinetics, cellular uptake, and cytotoxicity.

Main Results:

• Fluorination created a specific design window for compact, non-amyloid fibrillar architectures, rather than monotonic enhancement of assembly.
• MD simulations showed fluorine modulates hydrophobic interactions and hydration, disrupting beta-sheet packing.
• The optimized trifluorinated conjugate demonstrated high drug loading, pH-triggered release, specific cellular uptake, and low cytotoxicity.

Conclusions:

• Fluorinated peptide segments are a novel, programmable tool for rational design of peptide nanocarriers.
• Controlled fluorination allows precise tuning of nanocarrier structure and biological performance.
• This approach overcomes previous limitations in using fluoropeptides for functional nanomaterials.