Triglyceride-mimetic prodrugs: design principles, structural optimization, and implications for lymphatic transport and oral bioavailability

Triglyceride (TG)-mimetic prodrugs represent an innovative drug delivery strategy. Through chemical modification, drugs are conjugated to the TG backbone to enhance lymphatic transport capacity and oral bioavailability. This design effectively circumvents first-pass hepatic metabolism, promotes drug accumulation in the mesenteric lymph, and consequently enhances bioavailability. This review summarizes the design principles and advantages of TG-mimetic prodrugs, as well as their applications to drugs with diverse physicochemical properties, with a particular emphasis on how the structural features of TG-mimetic prodrugs influence their in vivo behavior. By optimizing the structure of TG prodrugs, their stability, lymphatic targeting ability, and bioavailability can be significantly improved, thereby providing a robust theoretical foundation and novel insights for the development of future drug delivery systems.