P-SElectin-targeting Fucoidan Nanoparticles Enable Combined NAC delivery and neutrophil recruitment blockade in acetaminophen-induced liver injury.

N-Acetylcysteine (NAC) is the only approved antidote for acetaminophen-induced liver injury (AILI), but its clinical benefit is largely restricted to the early stage of disease. In delayed-treatment AILI, massive neutrophil infiltration further aggravates liver damage, highlighting the need for therapeutic strategies that not only scavenge oxidative stress but also regulate inflammatory cell recruitment. Herein, we developed fucoidan-based NAC-loaded nanoparticles (NAC-FD NPs) to target P-selectin overexpressed on inflamed vascular endothelial cells. Through fucoidan-P-selectin interactions at the inflammatory vascular biointerface, NAC-FD NPs selectively accumulated at injured hepatic sites and enabled localized NAC delivery. More importantly, occupation of P-selectin binding sites competitively disrupted the PSGL-1/P-selectin-mediated adhesion cascade, thereby inhibiting neutrophil adhesion to endothelial cells and subsequent transendothelial migration. In a murine model of delayed-treatment AILI, NAC-FD NPs markedly reduced neutrophil accumulation in injured liver tissue and achieved significant therapeutic efficacy. By integrating the antioxidant activity of NAC with biointerface-mediated blockade of neutrophil recruitment, this nanoplatform simultaneously suppressed pathogenic events involved in both the early and late stages of AILI progression. These findings provide a promising biointerface-oriented strategy for the treatment of delayed-treatment AILI and broaden the therapeutic potential of targeted nanomedicine for inflammatory liver injury.