Engineered vesicles enhance oral antibiotic absorption in proximal small intestine and mitigate gut dysbiosis.

Oral antibiotics are a mainstay for treating bacterial infections, but unabsorbed portions can reach the caecum and colon, leading to gut dysbiosis. Herein, we engineer a biohybrid delivery system through the integration of milk extracellular vesicles with liposomes. The hybrid vesicles employ targeting mechanisms via neonatal Fc receptor and peptide transporter 1, facilitating antibiotic transport across the proximal small intestine. These vesicles exhibit superior drug encapsulation efficiency, stable release behavior, efficient mucus traversal, higher endocytosis, increased basolateral exocytosis, and improved oral absorption, achieving a 3.24-fold increase in oral bioavailability compared to free antibiotics. In lung bacterial infections and bacteremia models, hybrid vesicle-encapsulated cefdinir outperforms free antibiotics in eliminating infections. Notably, this approach also mitigates adverse effects on the intestinal microbiota, safeguarding the animals from dysbiosis-associated metabolic syndromes and opportunistic pathogen infections. This innovative hybrid vesicle system holds promise for the oral delivery of other drugs that suffer from limited absorption or cause gut dysbiosis.