Halting Mitochondrial Domino Effect in Acute Liver Injury: Polyphenol‐Sr Nanodrugs Attenuate Cell Death and Sterile Inflammation by Combating ROS Burst and Calcium Overload

ABSTRACT Acute liver injury (ALI) is a significant clinical cause of liver failure, potentially occurring at any stage of liver disease and posing a considerable health burden. One prevalent model of ALI stems from acetaminophen (APAP) overdose, where a vicious cycle of “mitochondrial damage‐inflammation amplification” and limited availability of small molecular drugs hinder current therapeutic approaches. Herein, a novel tannic acid (TA)‐strontium (Sr) nanodrug (SrTA) is proposed. With liver‐accumulating and mitochondria‐targeting capabilities, SrTA effectively harnesses the broad‐spectrum antioxidant properties of TA along with the calcium homeostasis‐regulating function of Sr 2+ . And its therapeutic efficacy surpassed that of an equivalent dose of N‐acetylcysteine (NAC). Mechanistically, SrTA directly scavenges mitochondrial reactive oxygen species (ROS), protects mitochondrial integrity, and alleviates endoplasmic reticulum (ER) stress and intracellular oxidative damage. Additionally, SrTA antagonizes calcium signaling, reduces the formation of mitochondria‐ER contacts, and inhibits mitochondrial calcium overload. By safeguarding mitochondrial function and preventing the aberrant opening of the mitochondrial permeability transition pore (mPTP), SrTA significantly curtail hepatocyte death and mitigates mtDNA‐induced sterile inflammation, effectively halting the injury cascade. In conclusion, this study presents a novel therapeutic strategy for ALI that targets mitochondria and synergistically regulates ROS bursts and calcium overload, achieving multifaceted therapeutic effects.