<p>Several pathophysiological conditions are associated to the protein misfolding leading to the protein aggregation which results amyloid fibrils formation and their deposition, the key pathological hallmark of amyloidopathies. Hence, inhibiting the amyloid genesis can be important therapeutics against amyloidosis. Exploration and identification of small molecules (polyphenols, flavonoids, small organic molecules, etc.) specifically polymeric nano-sized materials can prevent/delay amyloid fibrillation and, hence, serve as possible effective inhibitors against amyloidosis. So, in this study, we tried to investigate the mechanistic understanding of the aggregation processes. The present study is aimed at evaluating mechanistic insight into the anti-amyloidogenic potential of montmorillonite K-10 nanocomposites functionalized with o-phenylenediamine polymer on human serum albumin and human lysozyme by using various biophysical approaches including turbidity measurements, fluorescence assays (thioflavin T and ANS), circular dichroism, and dye binding assay (Congo red). Results obtained from fluorescence assays demonstrated that fibrillation of amyloid protein was inhibited effectively by clay nanocomposites coated with o-phenylenediamine polymer in a dose-dependent manner. Circular dichroism data showed that the secondary structural transition from α-helix to β-sheet was remarkably suppressed by all the NCs, and in particular, by the PoPD: MMT-1:1 NCs. Results suggested that the human serum albumin and human lysozyme fibrillation might be inhibited due to the presence of hydrophobic interfaces between the amino acid residues of protein fibrils and the clay nanocomposite aggregation inhibitors. We concluded that the polymer-conjugated clay nanocomposites can serve as a potential aggregation inhibitor that can aid in the amyloidopathy prevention.</p>