Assembling peptides for treating Alzheimer's disease: a supramolecular perspective

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current clinical treatments for AD primarily focus on alleviating symptoms but still face limitations such as suboptimal efficacy, side effects, and irreversible neuronal loss. Misfolding of the Aβ peptide plays a key role in AD pathogenesis and progression. By targeting this AD pathology, peptide-based therapeutics, particularly peptide assembly strategies, hold immense potential in AD therapy. Unlike sequence-based conventional reviews, this review reorganizes relevant advances from the perspective of a unified supramolecular framework. We first illustrate the structural, kinetic, and thermodynamic molecular basis of the pathological Aβ assembly and its neurotoxicity. Three mainstream supramolecular intervention strategies are then discussed: peptides redirecting the regulation of aberrant Aβ assembly, neuroprotective peptide scaffolds, and drug-loading peptide hydrogels. Finally, a universal rational design workflow for multifunctional peptide therapeutics is summarized, and perspectives on advanced directions are outlined.