Impact of Inorganic Nanoparticles on the Phenylalanine Self-Assembly: Implication for Phenylketonuria

Abstract

Phenylketonuria (PKU) is an inherited metabolic disorder caused by deficiency of phenylalanine hydroxylase, resulting in excessive accumulation of phenylalanine inside the body. Accumulation of it shows metabolic and cytotoxicity, high concentration of phenylalanine undergoes spontaneous self-assembly under physiological conditions, forming ordered amyloid-like aggregates stabilized by aromatic π–π interactions, hydrogen bonding, and hydrophobic forces, with fibrillary morphology similar to pathological amyloids. Phenylalanine aggregates can induce oxidative stress, membrane disruption, and neuronal damage, providing a molecular explanation for neurological impairments observed in PKU even under dietary management. Currently, PKU management primarily relies on lifelong dietary restriction of phenylalanine, supplementation with amino acid mixtures, tetrahydrobiopterin (BH4) therapy in responsive patients, and enzyme substitution approaches such as PEGylated phenylalanine ammonialyase. While these strategies effectively reduce systemic phenylalanine levels and improve cognitive outcomes when initiated early, they do not directly address phenylalanine aggregation or its cellular toxicity, potentially contributing to residual neurological deficits in treated individuals. Moreover, these are extremely costly therapies for the disorder. While, Inorganic nanoparticles offer a promising avenue to modulation of pathological self-assembly structurers by interfering with the aggregation process by their tunable size, surface chemistry, and multi-functionality. Nanoparticles can bind to amino acid monomers or oligomers, and disrupt the π–π stacking and hydrogen-bonding networks essential for fibril nucleation and growth. Enable sequestration of phenylalanine aggregates, and reduce formation of the assemblies, similar to protein amyloid. Compared to conventional therapies, primarily lower concentration of nanoparticle-based strategies directly targets the supramolecular assembly process. Providing potential advantages in early intervention and reducing long-term toxicity.