Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore.
College of Biological Sciences, University of Minnesota, Minneapolis, Minnesota 55455, United States.
ACS Nano. 2024 Jun 18;18(24):15452-15467. doi: 10.1021/acsnano.3c09206. Epub 2024 Jun 3.
Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction, as well as autophagic and mitochondrial impairments. Here, we report a series of biodegradable poly(butylene tetrafluorosuccinate--succinate) polyesters, comprising a 1,4-butanediol linker and varying ratios of tetrafluorosuccinic acid (TFSA) and succinic acid as components, to engineer lysosome-acidifying nanoparticles (NPs). The synthesized NPs are spherical with diameters of ≈100 nm and have low polydispersity and good stability. Notably, TFSA NPs, which are composed entirely of TFSA, exhibit the strongest degradation capability and superior acidifying properties. We further reveal significant downregulation of lysosomal vacuolar (H+)-ATPase subunits, which are responsible for maintaining lysosomal acidification, in human T2D pancreatic islets, INS-1 β-cells under chronic lipotoxic conditions, and pancreatic tissues of high-fat-diet (HFD) mice. Treatment with TFSA NPs restores lysosomal acidification, autophagic function, and mitochondrial activity, thereby improving the pancreatic function in INS-1 cells and HFD mice with lipid overload. Importantly, the administration of TFSA NPs to HFD mice reduces insulin resistance and improves glucose clearance. These findings highlight the therapeutic potential of lysosome-acidifying TFSA NPs for T2D.
2 型糖尿病（T2D）是一种常见的代谢紊乱疾病，缺乏有效的治疗方法，与溶酶体酸化功能障碍以及自噬和线粒体损伤有关。在这里，我们报告了一系列可生物降解的聚（丁烯四氟琥珀酸-琥珀酸）聚酯，由 1,4-丁二醇连接子和不同比例的四氟琥珀酸（TFSA）和琥珀酸组成，用于构建溶酶体酸化纳米颗粒（NPs）。合成的 NPs 呈球形，直径约为 100nm，具有低多分散性和良好的稳定性。值得注意的是，完全由 TFSA 组成的 TFSA NPs 具有最强的降解能力和优越的酸化性能。我们进一步揭示了人类 T2D 胰岛、慢性脂毒性条件下的 INS-1β细胞以及高脂肪饮食（HFD）小鼠的胰腺组织中，负责维持溶酶体酸化的溶酶体液泡（H+）-ATP 酶亚基显著下调。用 TFSA NPs 处理可恢复溶酶体酸化、自噬功能和线粒体活性，从而改善 INS-1 细胞和脂质过载的 HFD 小鼠的胰腺功能。重要的是，TFSA NPs 对 HFD 小鼠的给药可降低胰岛素抵抗并改善葡萄糖清除率。这些发现强调了用于 T2D 的溶酶体酸化 TFSA NPs 的治疗潜力。
