MOR-107

Protein misfolding and aggregation of human islet amyloid polypeptide (hIAPP) are central to β‐cell dysfunction in type 2 diabetes mellitus (T2DM). Despite many antiamyloid strategies, most suffer from poor selectivity, limited potency, and inadequate biocompatibility. Here, we report the first demonstration that polymeric Janus nanorods (JNRs) can delay both oligomerization and fibrillation of hIAPP through high‐affinity, sequence‐specific interactions. These anisotropic poly(N, N‐dimethylacrylamide) nanostructures, synthesized via reversible addition fragmentation chain transfer polymerization, self‐assemble to display a β‐hairpin mimetic ligand (LP2) on one face, enabling multivalent and directional binding. Biophysical assays reveal that JNR‐LP2 suppresses amyloid aggregation at substoichiometric concentrations, markedly outperforming free LP2 and nonfunctionalized JNRs. Mechanistic studies, including capillary zone electrophoresis and Thioflavin T fluorescence, show that JNR‐LP2 stabilizes monomeric hIAPP, prevents oligomer formation, and delays fibril nucleation. Importantly, binding experiments provide the first quantitative evidence of a strong affinity constant between a polymeric nanoparticle and hIAPP, establishing molecular specificity with negligible off‐target activity against unrelated amyloid proteins such as Tau. In cellular models, JNR‐LP2 mitigates hIAPP‐induced cytotoxicity while exhibiting excellent intrinsic biocompatibility. Collectively, these findings identify JNRs as a modular and selective nanoplatform for amyloid inhibition, offering a novel precision‐nanomedicine approach to T2DM.