Polypyrrole nanozymes with cell-free DNA scavenging and ferroptosis inhibition capabilities for the treatment of acetaminophen-induced acute liver injury

Acute liver failure (ALF) can result from the progressive development of acute liver injury triggered by acetaminophen (APAP) overdose. The core mechanisms involve an imbalance in the antioxidant system and upregulation of the inflammatory response, which collectively induce ferroptosis/apoptosis. Herein, nanozymes (PPy-Mg NPs) were synthesized through coordination reaction between polypyrrole nanoparticles (PPy NPs) and magnesium ions. The enriched PPy-Mg NPs were explored as active anti-inflammatory nanozymes for effective acute liver injury treatment. Enriched cationic PPy-Mg NPs in the liver effectively scavenged excess reactive oxygen and nitrogen species (RONS) and cell-free DNA. It is worth emphasizing that in the delayed AILI mouse models, bioactive PPy-Mg NPs not only reduced oxidative stress levels but also modulated multiple biological signaling pathways, such as NF-κB, Nrf2-Keap1, ferroptosis/apoptosis. The research indicates the possible medical application of PPy-Mg NPs nanozymes in efficient enrichment treatment for acute liver injury. Statement of Significance APAP-induced liver injury (AILI) can progress to acute liver failure (ALF), presenting a significant clinical challenge. Currently, N-acetylcysteine (NAC) is the only medication approved treatment; however, its efficacy in patients with advanced AILI remains unsatisfactory. Therefore, the development of new therapeutics for the treatment of AILI are crucial. This work developed a PPy-Mg NPs nanozyme for the efficient AILI treatment. PPy-Mg NPs provide constructive applications of polypyrrole-based nanozymes for AILI treatment, which covers upstream metabolic rescue (RONS scavenging), necrotic debris clearance (cfDNA removal), and residual cell protection (ferroptosis inhibition) across temporal and spatial dimensions, holds potential for extending therapeutic windows and enhancing protection rates in high-risk/complex cases.