Natural Nanoparticles in Gegen–Qinlian Decoction Promote the Colonic Absorption of Active Constituents in Mice with Dextran Sulfate Sodium-Induced Ulcerative Colitis

<b>Background/Objectives</b>: The aim of this study was to reveal the influence of the natural nanoparticles (Nnps) isolated from Gegen-Qinlian Decoction (GQD), i.e., GQD-Nnps, on the intestinal absorption and pharmacokinetic properties of several representative active GQD constituents. <b>Methods</b>: The morphology of GQD-Nnps was examined using scanning electron microscopy (SEM). Protein and polysaccharide contents were measured using the bicinchoninic acid (BCA) assay and phenol-sulfuric acid method, respectively. Major GQD constituents were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Formation mechanisms were explored using dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), and high-resolution mass spectrometry (HRMS). Pharmacokinetic studies were conducted in mice with dextran sulfate sodium (DSS)-induced UC. <b>Results</b>: GQD-Nnps were spherical, with a size of 110.9 ± 8.1 nm and a zeta potential of -13.7 ± 1.5 mV. GQD-Nnps were primarily composed of proteins and polysaccharides. FTIR analysis revealed significant hydrogen bonding interactions between the small molecular and macromolecular constituents of GQD. HRMS analyses indicated complex formation among small molecules, particularly berberine, baicalin, and glycyrrhizic acid. DLS demonstrated good stability of GQD-Nnps in artificial gastric and intestinal fluids. Pharmacokinetic studies showed that, except for puerarin, blood and liver exposure levels of several constituents in the GQD-Nnps group were significantly higher than those in the GQD extract group, suggesting enhanced colonic absorption and hepatic distribution. <b>Conclusions</b>: GQD-Nnps create an oral drug delivery system through complex interactions, significantly enhancing the colonic absorption and hepatic distribution of several active GQD constituents.