Amino Acid-Driven Gold Nanochaperone Platforms for Alzheimer's Therapy: A Mechanistic and Design Framework for Protein Misfolding Modulation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the misfolding and aggregation of amyloid-β (Aβ) peptides and tau proteins, leading to synaptic dysfunction and neuronal degeneration. Despite decades of therapeutic development, currently available treatments provide limited disease modification, largely due to the structural heterogeneity of Aβ aggregates, poor blood-brain barrier penetration and insufficient targeting of toxic oligomeric intermediates. Recently, nanotechnology-based strategies have emerged as promising approaches to modulate pathological protein aggregation. Among these, gold nanoparticle (AuNP)-based nanochaperones have attracted considerable attention due to their tunable physicochemical properties, multivalent binding capabilities and high biocompatibility. In particular, amino acid-functionalized AuNPs provide a biologically inspired platform capable of mimicking molecular chaperone interactions with misfolded proteins. These systems can modulate Aβ aggregation through electrostatic interactions, hydrophobic effects, π-π stacking, hydrogen bonding and metal-ligand coordination, enabling selective targeting of monomers, oligomers and fibrillar aggregates. In this review, we synthesize current advances in amino acid-engineered gold nanochaperones and analyze their mechanisms of interaction with Aβ species. This review integrates mechanistic insights and design considerations to highlight how amino acid-functionalized gold nanoparticles can be optimized for modulating amyloid-β aggregation. In addition, we critically evaluate key translational challenges such as blood-brain barrier delivery, biodistribution, nanotoxicology, protein corona formation and clinical development considerations. By bridging molecular mechanisms with engineering design principles, this review provides a strategic roadmap for the development of next-generation nanochaperone therapeutics targeting protein misfolding in Alzheimer's disease. Overall, amino acid-engineered gold nanochaperones represent a promising frontier in nanomedicine for selectively modulating pathological protein aggregation and developing disease-modifying therapies for Alzheimer's disease.