Design of biomimetic chylomicrons based on 1,3-diolein grafted hyaluronic acid to drive biomacromolecules across the intestinal mucosal barrier.

Oral delivery of biomacromolecule drugs faces significant challenges due to low absorption efficiency. Inspired by the natural absorption pathway of dietary triglycerides via chylomicrons, bionic nanoparticles based on 1,3-diolein grafted hyaluronic acid (HA-DOG) were developed to overcome the oral delivery barriers and influence of structural characteristics on the oral fate of exenatide were systematically investigated. Self-assembled exenatide nanocores (EAZ NPs) were encapsulated within HA-DOG to form core-shell nanoparticles (HA-DOG/EAZ NPs). These nanoparticles demonstrated enhanced enzymatic stability and improved mucosal penetration, leading to a 5.6-fold increase in intestinal permeability compared to EAZ NPs alone. HA-DOG/EAZ NPs with high substitution degrees showed better lymphatic targeting and increased exenatide accumulation in the pancreas. In vivo studies revealed that HA-DOG/EAZ NPs achieved a 9.67 % pharmacological bioavailability and exhibited a persistent hypoglycemic effect in type 2 diabetic rats. This study presents a promising strategy for the oral delivery of biomacromolecule drugs, particularly GLP-1 receptor agonists, by mimicking the chylomicron pathway and overcoming key gastrointestinal barriers.