The folding of synthetic polymers into single chain nanoparticles (SCNPs) draws inspiration from the precise folding of amino acid chains into proteins. Most SCNPs reported to date, however, are made using synthetic polymers lacking biodegradability and secondary structure, thus limiting their resemblance to proteins.
Polypeptides are an ideal alternative because they are biodegradable and have an inherent tendency to form secondary structures. In this work, we introduce two new approaches for synthesizing SCNPs using polypeptides. In the first approach, we used poly-L-glutamic acid (PLGA), a polymer known to adopt either a random coil confirmation or alpha helices depending on pH, and an intramolecular crosslinking strategy to produce SCNPs between 10 to 15 nm depending on the degree of crosslinking and solvent conditions.
In the second approach, we again use PLGA but introduce phenylalanine as an aromatic hydrophobic comonomer. Phenylalanine naturally tends to form hydrophobic domains, which play a crucial role in proteins by helping them achieve and maintain a stable three-dimensional structure. This happens because hydrophobic interactions and π-π stacking minimize entropic loss and promote compact folding. Inspired by this, we aim to investigate how the presence of phenylalanine influences the structural properties of SCNPs. To achieve this, we use a range of analytical techniques to assess how phenylalanine impacts the self-assembly, secondary structure, and stability of SCNPs. These findings open new possibilities for developing SCNP-based platforms for efficient and controlled drug delivery, particularly in crossing tight junctions such as Blood Brain Barrier (BBB).