Reactive oxygen species-responsive liver-targeting nanoparticles enhance the therapeutic effect of baicalin magnesium in metabolic dysfunction-associated fatty liver disease

The interplay between lipid buildup, oxidative stress, and inflammatory responses is the key mechanism underlying metabolic dysfunction-associated fatty liver disease (MAFLD). We previously discovered that baicalin magnesium (BA-Mg), the natural form of baicalin in Scutellaria baicalensis Georgi, can alleviate liver damage through lipid-lowering, antioxidation, and anti-inflammatory effects. However, its hepatic distribution after injection is suboptimal. Therefore, we aimed to increase the hepatic BA-Mg content and thereby enhance its therapeutic effect. In this study, Gal-PEG_10K-TK-PCL_15K polymer was prepared as a carrier and the compound emulsion solvent evaporation method was adopted to generate Gal-PEG_10K-TK-PCL_15K@BA-Mg ROS-responsive liver inflammation-targeted nanoparticles. The formulation and preparation process were optimized through single-factor analysis and Box-Behnken design; structural characterization, assessment of stability and reactive oxygen species (ROS) sensitivity, and pharmacodynamic evaluation were also carried out. These nanoparticles showed 151.4 ± 1.48 nm size, 92.25 ± 0.40 % encapsulation efficiency (EE), and 26.55 ± 0.48 % drug loading capacity (DL). The nanoparticle emulsion demonstrated good stability at 4°C and an excellent ROS response under 1 mM H₂O₂. This preparation could significantly alleviate liver inflammation, oxidative stress, and lipid deposition in MAFLD mice, and its therapeutic effect was superior to that of BA-Mg. Overall, Gal-PEG_10K-TK-PCL_15K@BA-Mg ROS-responsive liver-targeted nanoparticles could increase the liver concentration of BA-Mg, thereby enhancing its therapeutic effect on MAFLD.