Cysteine-Derived Chiral Carbon Quantum Dots: A Fibrinolytic Activity Regulator for Plasmin to Target the Human Islet Amyloid Polypeptide for Type 2 Diabetes Mellitus

The fibrillization and deposition of the human islet amyloid polypeptide (hIAPP) are the pathological hallmark of type 2 diabetes mellitus (T2DM), and these insoluble fibrotic depositions of hIAPP are considered to strongly affect insulin secretion by inducing toxicity toward pancreatic islet fi-cells. The current strategy of preventing amyloid aggregation by nanoparticle-assisted inhibitors can only disassemble fibrotic amyloids into more toxic oligomers and/or protofibrils. Herein, for the first time, we propose a type of cysteine-derived chiral carbon quantum dot (CQD) that targets plasmin, a core natural fibrinolytic protease in humans. These CQDs can serve as fibrinolytic activity regulators for plasmin to cleave hIAPP into nontoxic polypeptides or into even smaller amino acid fragments, thus alleviating hIAPP's fibrotic amyloid-induced cytotoxicity. Our experiments indicate that chiral CQDs have opposing effects on plasmin activity. The L-CQDs promote the cleavage of hIAPP by enhancing plasmin activity at a promotion ratio of 23.2%, thus protecting fi-cells from amyloid-induced toxicity. In contrast, the resultant D-CQDs significantly inhibit proteolysis, decreasing plasmin activity by 31.5% under the same reaction conditions. Second harmonic generation (SHG) microscopic imaging is initially used to dynamically characterize hIAPP before and after proteolysis. The L-CQD promotion of plasmin activity thus provides a promising avenue for the hIAPP-targeted treatment of T2DM to treat low fibrinolytic activity, while the D-CQDs, as inhibitors of plasmin activity, may improve patient survival for hyperfibrinolytic conditions, such as those existing during surgeries and traumas.

Automated summary

The fibrillization and deposition of hIAPP are pathological features of T2DM. Currently, nanoparticle-assisted inhibitors can only disassemble fibrotic amyloids into more toxic oligomers/protofibrils. Here, we propose cysteine-derived chiral CQDs that target plasmin, a natural fibrinolytic enzyme. L-CQDs enhance plasmin activity, promoting hIAPP cleavage and protecting fi-cells. D-CQDs inhibit proteolysis, reducing plasmin activity and may be beneficial for hyperfibrinolytic conditions.