Yang Yongzhen, Wang Qin, Li Gongjian, Guo Wenjing, Yang Zuojun, Liu Hao, Deng Xiaoyuan
MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou510631, China.
Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou510631, China.
ACS Appl Mater Interfaces. 2023 Jan 18;15(2):2617-2629. doi: 10.1021/acsami.2c17975. Epub 2023 Jan 3.
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 β-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 β-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.
人胰岛淀粉样多肽（hIAPP）的纤维化和沉积是2型糖尿病（T2DM）的病理标志，这些hIAPP不溶性纤维化沉积物被认为通过诱导对胰岛β细胞的毒性而强烈影响胰岛素分泌。目前通过纳米颗粒辅助抑制剂预防淀粉样聚集的策略只能将纤维化淀粉样蛋白分解成毒性更强的寡聚体和/或原纤维。在此，我们首次提出了一种靶向纤溶酶（人类核心天然纤维蛋白溶解蛋白酶）的半胱氨酸衍生手性碳量子点（CQD）。这些CQDs可作为纤溶酶的纤维蛋白溶解活性调节剂，将hIAPP切割成无毒多肽或更小的氨基酸片段，从而减轻hIAPP纤维化淀粉样蛋白诱导的细胞毒性。我们的实验表明，手性CQDs对纤溶酶活性有相反的影响。l-CQDs通过以23.2%的促进率增强纤溶酶活性来促进hIAPP的切割，从而保护β细胞免受淀粉样蛋白诱导的毒性。相比之下，所得的d-CQDs显著抑制蛋白水解，在相同反应条件下使纤溶酶活性降低31.5%。二次谐波产生（SHG）显微镜成像最初用于动态表征蛋白水解前后的hIAPP。因此，l-CQD对纤溶酶活性的促进为以hIAPP为靶点治疗T2DM以治疗低纤维蛋白溶解活性提供了一条有前景的途径，而d-CQDs作为纤溶酶活性抑制剂，可能提高高纤维蛋白溶解状态（如手术和创伤期间存在的状态）患者的生存率。
