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.