An oral carrier-free nanodrug’s synergistic mechanisms analyzed in silico and in experiment: assembly ability, pH tolerance capability, mucus layer permeability

Despite their promising potential as simplified and highly efficient therapeutic platforms, carrier-free nanodrugs remain limited by an incomplete explanation of the molecular mechanisms that govern their co-assembly, structural stability, and biological interactions. This knowledge gap impedes rational guidance for preliminary drug selection in carrier-free nanodrug development, especially for oral administration, where navigating the complex gastrointestinal environment is a major barrier to absorption. Here, a glycyrrhizic acid-baicalin nanodrug (GBN) was chosen as representative carrier-free nanodrug model. It exhibits emergent properties including the enhanced efficacy and effective oral delivery by overcoming gastrointestinal barriers. Experimental characterization and molecular simulations revealed that GBN exhibited stable pharmaceutical properties, and its greater thermodynamic and kinetic stability than self-assembly endowed it with potent assembly ability and sustained assembly ability at different pH levels. An integrated computational framework combining gastrointestinal pH-response modeling with a mesoscopic intestinal mucus model was also established and further enabled quantitative assessment of GBN stability and mucus permeability. Overall, this study established a comprehensive simulation-experiment framework for evaluating the assembly ability and oral delivery mechanisms of carrier-free nanodrugs, expecting to provide a comprehensive analysis for evaluating the assembly ability and oral delivery mechanisms of nanodrugs.