Ultra-small quercetin-based nanotherapeutics ameliorate acute liver failure by combatting inflammation/cellular senescence cycle

<b>Background:</b> Acute liver failure (ALF) is marked by a substantial generation of reactive oxygen species (ROS), which can induce both cellular senescence and a pronounced inflammatory response. Senescent cells secrete factors collectively termed the senescence-associated secretory phenotype (SASP), which exacerbate inflammation, while inflammation can reciprocally promote cellular senescence. Quercetin (Que), recognized for its ROS-scavenging capabilities, holds the potential for anti-inflammatory and anti-senescent effects. However, its extremely low aqueous solubility constrains its clinical efficacy in treating inflammation. <b>Methods:</b> We employed a simple and stable coordination method to synthesize ultra-small quercetin-Fe nanoparticles (QFN) by complexing quercetin with iron ions. The ROS-scavenging, anti-inflammatory, and anti-senescent effects of QFN were evaluated <i>in vitro</i>. A lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice model was used to investigate the therapeutic effects of QFN <i>in vivo</i>, and transcriptomic analysis was conducted to elucidate the mechanisms underlying QFN-mediated hepatoprotection. <b>Results:</b> Our findings demonstrate that QFN possesses remarkable water solubility and highly efficient ROS-scavenging properties. <i>In vitro</i>, QFN effectively inhibits macrophage-mediated inflammation and mitigates hepatocyte senescence. <i>In vivo</i>, QFN significantly attenuates LPS/D-GalN-induced ALF by protecting against macrophage inflammation and cellular senescence, thereby disrupting the self-perpetuating cycle of inflammation and aging. Moreover, its potent ROS scavenging capacity not only suppresses cellular apoptosis but also facilitates liver regeneration. Transcriptomic analyses further reveal that QFN exerts its protective effects through the modulation of key pathways involved in cellular senescence and inflammation. <b>Conclusions:</b> In summary, our study characterizes QFN as a potent ROS-scavenging modulator that exhibits both anti-inflammatory and anti-senescent properties, effectively disrupting the detrimental feedback loop between inflammation and cellular senescence. QFN holds considerable potential as a therapeutic agent for the treatment of ALF and other pathologies associated with inflammation and aging.