PLGA nanoparticles encapsulating fibroblast growth factor 21 alleviate acetaminophen-induced acute liver injury

The short half-life of fibroblast growth factor 21 (FGF21) in vivo limits its clinical application in acetaminophen (APAP)-induced acute liver injury (ALI). This study aimed to construct a novel PLGA-based nanoparticle delivery system for FGF21 and to investigate its protective effects and underlying mechanisms in APAP-induced ALI. PLGA-FGF21 nanoparticles were prepared using a double-emulsion solvent evaporation method and characterized by transmission electron microscopy and Zetasizer Nano for morphology, size, and stability. Their release profile and cytotoxicity were evaluated in vitro using AML12 cells, while hepatoprotective effects were assessed in an APAP-induced ALI mouse model. Histopathology, biochemical assays, immunofluorescence, and Western blot were employed to examine liver function, oxidative stress, and molecular mechanisms. The nanoparticles displayed uniform spherical morphology with an average size of 222.04 ± 1.08 nm and remained stable for 7 days in aqueous suspension. Encapsulation conferred sustained-release properties, and the particles showed no cytotoxicity while maintaining biological activity for at least 28 days. In vivo, PLGA-FGF21 significantly alleviated APAP-induced liver damage, reduced serum ALT and AST, and exhibited superior hepatoprotective efficacy compared with free FGF21. Furthermore, it suppressed inflammatory responses by decreasing TNF-α and MDA levels, while enhancing antioxidant defenses through increased SOD activity. Mechanistically, PLGA-FGF21 activated the PGC-1α/Nrf2/HO-1 signaling pathway, contributing to enhanced anti-inflammatory and antioxidant effects. PLGA-FGF21 nanoparticles provide potent protection against APAP-induced ALI by reducing inflammation and oxidative stress, which may be associated with activation of the PGC-1α/Nrf2 signaling pathway, offering a promising strategy for FGF21-based therapy in liver injury.