Poly-arginine-11 (R11) Edge-Grafting Preserves Aromatic Drug Loading on Graphene Nanocarriers

Effective drug delivery often faces challenges with cellular membrane permeability, a barrier that cell-penetrating peptides (CPPs) are known to overcome. While CPPs enhance cellular uptake, their functionalization on nanocarriers can interfere with drug loading, especially when drugs bind via noncovalent π-π interactions on surfaces like graphene. This conflict arises because peptide grafting might occupy or alter the very surface required for drug adsorption. Addressing this, researchers sought an orthogonal functionalization strategy to leverage CPP benefits without compromising the crucial π-conjugated molecule binding sites on graphene-based nanocarriers.

Researchers developed an orthogonal functionalization strategy, covalently immobilizing Poly-arginine-11 (R11) selectively at the carboxylic acid-rich edges of graphene nanoparticles (B60). This design aimed to preserve the basal plane for π-π interactions. They then evaluated the loading and thermally induced release of two π-conjugated cargo molecules: 1-pyrenecarboxylic acid and compound 8, a NEK6 inhibitor. Spectroscopic and microscopic analyses were employed to confirm the integrity and accessibility of the basal plane post-functionalization, complemented by Molecular dynamics simulations to model peptide chain behavior and interactions with the graphene surface.

The study demonstrated that R11 grafting at the edges of graphene nanoparticles did not affect the loading capacity or thermally induced release of aromatic drugs. Spectroscopic and microscopic analyses confirmed that the basal plane remained intact and accessible for π-π interactions after peptide functionalization. Molecular dynamics simulations provided insights into the mechanism, indicating that the R11 peptide chains formed a flexible, charged corona specifically at the nanoparticle periphery. This peripheral localization was crucial, as it prevented any perturbation of the molecule-graphene interactions essential for drug binding.

This orthogonal functionalization strategy successfully preserved the aromatic surface for π-π interactions, allowing for efficient drug binding while incorporating a cell-penetrating peptide.