A validated criterion for engineering 0D@2D nanocomposite to modulate amyloid peptide self-assembly and fibril disassembly

2D nanosheets-supported 0D nanoparticles (NPs@NSs), a typical 0D/2D nanocomposite, possess unique capabilities to modulate biological processes through non-covalent nano-bio interfacial interactions. However, the underlying molecular basis, particularly the validated criteria for quantifying the non-covalent nano-bio interfacial interaction, remain to be elucidated. In this study, we quantified the non-covalent nano-bio interfacial affinity-energies of NPs@NSs with Alzheimer’s amyloid-β (Aβ) peptides, which were divided into 0D(NPs)-peptide (E 0D-p ) and 2D(NSs)-peptide (E 2D-p ) parts. Our results classified these interactions into three distinct ranges of E 0D-p /E 2D-p  < 1, ≈1, >1. Both simulations and experiments demonstrated that NPs@NSs with E 0D-p /E 2D-p  < 1 effectively inhibited Aβ fibrillization by stabilizing its monomeric native conformation and even disassembled mature Aβ-fibrils by disrupting their β-sheet structures; whereas NPs@NSs with E 0D-P /E 2D-P ≈1 or > 1 did not exhibit such effects. These findings for the first time provide microscopic molecular insights into the non-covalent nano-bio interfacial interactions between NPs@NSs and peptide chains and offer a validated criterion for engineering 0D/2D nanocomposites to modulate amyloid peptide self-assembly and fibril disassembly, which will enhance the development of nanomedicine for Alzheimer’s and other amyloid-related diseases.