Overcoming mucus trapping by engineering PEGylated self-nanoemulsions for enhanced oral absorption of a novel AMPK activator.

D100B is a first-in-class small-molecule activator of AMP-activated protein kinase (AMPK) that specifically targets the lysosomal pool, enabling precise metabolic regulation with lower systemic toxicity. Despite its favorable solubility and stability, D100B exhibits extremely poor oral bioavailability due to strong mucoadhesion and extensive retention within the intestinal mucus. Electrostatic and hydrophobic interactions between D100B and mucin were found to severely hinder its diffusion and epithelial absorption. To overcome this limitation, a PEGylated self-nanoemulsifying system (PSNE) was developed to reduce mucin binding and enhance mucus penetration. The optimized PSNE displayed uniform nanoscale droplets, sustained drug release, and significantly improved diffusion in simulated mucus. In Caco-2/HT29-MTX co-culture monolayers, PSNE significantly enhanced epithelial transport, while pharmacokinetic evaluation demonstrated a 2.66-fold increase in oral bioavailability compared with the unformulated drug. Overall, this study establishes a mucus-barrier-focused formulation strategy that may be applicable for improving the oral delivery of amphiphilic compounds whose absorption is compromised by mucus-mediated retention.