Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, P. R. China.
MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, P. R. China.
Adv Mater. 2023 Mar;35(11):e2208571. doi: 10.1002/adma.202208571. Epub 2023 Feb 5.
Excess accumulation of mitochondrial reactive oxygen species (mtROS) is a key target for inhibiting pyroptosis-induced inflammation and tissue damage. However, targeted delivery of drugs to mitochondria and efficient clearance of mtROS remain challenging. In current study, it is discovered that polyphenols such as tannic acid (TA) can mediate the targeting of polyphenol/antioxidases complexes to mitochondria. This affinity does not depend on mitochondrial membrane potential but stems from the strong binding of TA to mitochondrial outer membrane proteins. Taking advantage of the feasibility of self-assembly between TA and proteins, superoxide dismutase, catalase, and TA are assembled into complexes (referred to as TSC) for efficient enzymatic activity maintenance. In vitro fluorescence confocal imaging shows that TSC not only promoted the uptake of biological enzymes in hepatocytes but also highly overlapped with mitochondria after lysosomal escape. The results from an in vitro model of hepatocyte oxidative stress demonstrate that TSC efficiently scavenges excess mtROS and reverses mitochondrial depolarization, thereby inhibiting inflammasome-mediated pyroptosis. More interestingly, TSC maintain superior efficacy compared with the clinical gold standard drug N-acetylcysteine in both acetaminophen- and D-galactosamine/lipopolysaccharide-induced pyroptosis-related hepatitis mouse models. In conclusion, this study opens a new paradigm for targeting mitochondrial oxidative stress to inhibit pyroptosis and treat inflammatory diseases.
线粒体活性氧（mtROS）的过度积累是抑制细胞焦亡诱导的炎症和组织损伤的关键靶点。然而，将药物靶向递送至线粒体并有效清除 mtROS 仍然具有挑战性。在本研究中，发现多酚类物质（如单宁酸）可以介导多酚/抗氧化酶复合物靶向线粒体。这种亲和力不依赖于线粒体膜电位，而是源于单宁酸与线粒体外膜蛋白的强结合。利用单宁酸与蛋白质之间自组装的可行性，将超氧化物歧化酶、过氧化氢酶和单宁酸组装成复合物（称为 TSC），以维持高效的酶活性。体外荧光共聚焦成像显示，TSC 不仅促进了生物酶在肝细胞中的摄取，而且在溶酶体逃逸后与线粒体高度重叠。肝细胞氧化应激体外模型的结果表明，TSC 能有效清除过多的 mtROS 并逆转线粒体去极化，从而抑制炎症小体介导的细胞焦亡。更有趣的是，与临床金标准药物 N-乙酰半胱氨酸相比，TSC 在对乙酰氨基酚和 D-半乳糖胺/脂多糖诱导的细胞焦亡相关肝炎小鼠模型中均表现出更好的疗效。总之，该研究为靶向线粒体氧化应激抑制细胞焦亡和治疗炎症性疾病开辟了新的范例。
