线粒体靶向递送多酚介导的抗氧化酶复合物以对抗细胞焦亡和炎症性疾病,Advanced Materials

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线粒体靶向递送多酚介导的抗氧化酶复合物以对抗细胞焦亡和炎症性疾病
Advanced Materials ( IF 27.4 ) Pub Date : 2023-01-17 , DOI: 10.1002/adma.202208571
Jiaojiao Zhang _{1,

2} , Bingqiang Gao _{1,

3,

4,

5,

6,

7} , Binglin Ye _{1,

3,

4,

5,

6,

7} , Zhongquan Sun _{1,

3,

4,

5,

6,

7} , Zhefeng Qian ₂ , Lisha Yu _{1,

3,

4,

5,

6,

7} , Yanli Bi _{1,

3,

4,

5,

6,

7} , Lie Ma ₂ , Yuan Ding _{1,

3,

4,

5,

6,

7} , Yang Du _{1,

3,

4,

5,

6,

7} , Weilin Wang _{1,

3,

4,

5,

6,

7} , Zhengwei Mao _{1,

2,

3}

Affiliation

线粒体活性氧 (mtROS) 的过量积累是抑制细胞焦亡引起的炎症和组织损伤的关键目标。然而，将药物靶向递送至线粒体和有效清除 mtROS 仍然具有挑战性。在当前的研究中，发现单宁酸 (TA) 等多酚可以介导多酚/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 TA 与线粒体外膜蛋白的强结合。利用TA与蛋白质自组装的可行性，将超氧化物歧化酶、过氧化氢酶和TA组装成复合物（简称TSC），实现高效的酶活性维持。体外荧光共聚焦成像显示，TSC 不仅促进肝细胞生物酶的摄取，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 有效清除过量的 mtROS 并逆转线粒体去极化，从而抑制炎性体介导的细胞焦亡。更有趣的是，与临床金标准药物相比，TSC 保持了优越的疗效对乙酰氨基酚和 D- 半乳糖胺/脂多糖诱导的细胞焦亡相关肝炎小鼠模型中的N-乙酰半胱氨酸。总之，这项研究为靶向线粒体氧化应激以抑制细胞焦亡和治疗炎症性疾病开辟了一个新范例。

"点击查看英文标题和摘要"

Mitochondrial-Targeted Delivery of Polyphenol-Mediated Antioxidases Complexes against Pyroptosis and Inflammatory Diseases

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.

更新日期：2023-01-17

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