Prussian Blue Nanozyme as a Pyroptosis Inhibitor Alleviates Neurodegeneration

Abstract Current pharmacological interventions for Parkinson's disease (PD) remain unsatisfactory in clinical settings. Inflammasome‐mediated pyroptosis represents a potential therapeutic target for the alleviation of neurodegenerative diseases. The development of inflammasome‐mediated pyroptosis agonists or antagonists may transform the treatment of neurodegenerative diseases. However, the identification of specific compounds that inhibit pyroptosis remains challenging. Herein, Prussian blue nanozyme (PBzyme) is revealed as a pyroptosis inhibitor to alleviate the neurodegeneration in mouse and cell models of PD. PBzyme protects the microglia and neurons against 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). PBzyme alleviates motor deficits, attenuates the damage of mitochondrial membrane potential, and rescues dopaminergic neurons. Furthermore, intra‐cerebroventricular injection of PBzyme reduces dopaminergic degeneration and inhibits neuroinflammation in an MPTP‐induced PD mouse model. Both in vitro and in vivo results demonstrate that PBzyme reduces the activation of microglial nucleotide‐binding domain and leucine‐rich repeat family pyrin domain containing 3 (NLRP3) inflammasomes and caspase‐1 by scavenging reactive oxygen species, thereby downregulating gasdermin D (GSDMD) cleavage as well as inflammatory factor production, and eventually leading to the inhibition of microglia pyroptosis. Overall, this work highlights the neuroprotective effects of PBzyme as a pyroptosis inhibitor and provides valuable mechanistic insights and a potential therapeutic strategy for the treatment of PD.