2型糖尿病(T2D),缺乏有效治疗的普遍代谢紊乱,与溶酶体酸化功能障碍有关,以及自噬和线粒体损伤。这里,我们报道了一系列可生物降解的聚(四氟丁二酸丁二醇酯-共丁二酸酯)聚酯,包含1,4-丁二醇接头和不同比例的四氟琥珀酸(TFSA)和琥珀酸作为组分,设计溶酶体酸化纳米颗粒(NPs)。合成的NP为球形,直径为≈100nm,多分散性低,稳定性好。值得注意的是,TFSANP,完全由TFSA组成,表现出最强的降解能力和优越的酸化性能。我们进一步揭示了溶酶体空泡(H+)-ATP酶亚基的显著下调,负责维持溶酶体酸化,在人类T2D胰岛中,慢性脂毒性条件下的INS-1β细胞,和高脂饮食(HFD)小鼠的胰腺组织。用TFSANP治疗可恢复溶酶体酸化,自噬功能,和线粒体活动,从而改善INS-1细胞和HFD小鼠脂质超负荷的胰腺功能。重要的是,对HFD小鼠施用TFSANP可降低胰岛素抵抗并改善葡萄糖清除。这些发现强调了溶酶体酸化TFSANP对T2D的治疗潜力。
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-co-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.