Abstract Amyloid aggregation of islet amyloid polypeptide (IAPP) is associated with β-cell death in type-2 diabetes (T2D). IAPP, a peptide hormone co-secreted with insulin by β-cells, is one of the most amyloidogenic proteins and readily forms amyloid fibrils in vitro. Mounting evidence suggests that inhibition of IAPP aggregation and aggregation-mediated cytotoxicity, our long-term goal, is an attractive therapeutic strategy to prevent β-cell death and stop the progression of diabetic conditions in T2D. With the recent advances of Cryo-EM in Structural Biology, atomic structures of IAPP fibrils have been solved, comprised of parallel in-register β-sheets as the cross-β core. However, due to heterogeneous and transient nature of oligomer intermediates populated during aggregation, many details of the process from isolated monomers to final fibrils are still unknown. With amyloid toxicity likely mediated by direct or indirect interactions with the cell membrane, it is increasingly important to study the aggregation of IAPP in the membrane environment. Increasing evidence also suggests pathological correlations between different amyloid diseases – e.g., T2D is the risk factor of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases; and bacterial amyloids may contribute to the onset of neurodegenerative diseases and diabetes. Cross-interactions between different amyloid proteins at the molecular level might contribute to the pathological correlation between corresponding diseases. We have demonstrated that novel nanoparticles can be engineered to mitigate hIAPP aggregation and cytotoxicity. Despite many advantages including the ability to cross biological barriers, major concerns for nanomedicine development include potential toxicity associated with immune responses and the lack of specificity. In this MIRA renewal application, the PI proposes to continuously uncover molecular mechanisms of IAPP aggregation and to explore novel nanoparticle approaches to inhibit IAPP aggregation and toxicity in the following directions: 1) IAPP aggregation and interactions with the membrane; 2) cross-interactions between hIAPP and other amyloidogenic proteins; and 3) mitigation of IAPP amyloidosis with nanoparticles functionalized by endogenous inhibitors. The PI lab will combine computational modeling with experimental characterization and validation. Computational modeling can help bridge the time and length scale gaps between experimental observations and the underlying molecular systems, providing not only molecular insights to experimental observations but also offering experimentally-testable hypotheses. Such a combined computational and experimental approach can improve research efficiency and shorten discovery cycle. The outcome of the proposed studies will help understand disease mechanisms and discover novel therapeutic targets (Project 1); provide molecular bases for pathological correlations between T2D and other amyloid diseases, ...