Harnessing the apical sodium-dependent bile acid transporter for enhanced oral delivery of peptide drugs: mechanisms, strategies, and therapeutic potential

Oral administration of peptide drugs (PDs) faces significant challenges due to the harsh gastrointestinal environment and low intestinal epithelial permeability, leading to poor bioavailability. Current intestinal delivery pathways are often constrained by limited intestinal transport efficiency, which further hinders the effective delivery of PDs. The apical sodium-dependent bile acid transporter (ASBT) presents a promising target for enhancing the oral delivery of PDs. ASBT-mediated oral peptide delivery represents a transformative strategy by leveraging the transporter's high intestinal expression and active transport capacity, surpassing traditional passive/paracellular mechanisms. This review focuses on the emerging research on ASBT-based oral PDs delivery strategies, providing a comprehensive evaluation of the design concepts and principles that support these approaches and offering valuable insights for inspiring ASBT-based oral PDs delivery strategies to enhance bioavailability. Current strategies predominantly rely on passive transport or paracellular transport, which, despite being widely used, suffer from low transport efficiency. On the other hand, active transport via other intestinal transporters is often limited by transporter abundance and capacity. In contrast, ASBT-mediated transport offers a high-capacity, efficient, and safe mechanism with sufficient transporter expression in the intestine, making it a promising alternative for oral PDs delivery.