Engineered Bacteria as Living Materials Advance Oral Peptide Delivery for Metabolic, Inflammatory, Neurodegenerative Diseases, and Cancer

Oral delivery of peptide drugs is severely hampered by gastric acidity, rapid enzymatic degradation, and poor intestinal absorption, leading to extremely low bioavailability. This necessitates inconvenient parenteral administration for most peptide therapies. Overcoming these barriers is crucial for improving patient compliance and expanding therapeutic applications. Engineered bacteria offer a novel solution by colonizing the gastrointestinal tract and enabling localized, in situ synthesis and controlled release of therapeutic peptides, directly addressing the bioavailability challenge.

This review systematically summarized recent advances in engineered bacteria as "living functional materials" for oral peptide delivery. The authors focused on two key areas: optimizing bacterial chassis cells for enhanced stability and function within the gastrointestinal environment, and elucidating the diverse mechanisms of peptide release. Furthermore, the review comprehensively outlined the therapeutic applications of these bacterial systems across a wide spectrum of major diseases, providing a detailed overview of the current state and future directions in this rapidly evolving field.

The review highlighted how engineered bacteria effectively overcome significant physiological barriers, such as gastric acidity and enzymatic degradation, which severely limit the oral bioavailability of traditional peptide drugs. It detailed various strategies for optimizing bacterial chassis cells to improve their colonization and in situ synthesis capabilities within the gastrointestinal tract. Mechanisms of peptide release, including controlled and responsive delivery, were thoroughly discussed, emphasizing their role in sustained therapeutic effects. The authors systematically outlined the broad therapeutic utility of these systems, demonstrating their potential in treating metabolic diseases, inflammatory conditions, neurodegenerative disorders, and cancer.

Engineered bacteria enable in situ synthesis and release of therapeutic peptides, offering an effective strategy to overcome bottlenecks in oral peptide delivery. The review also explored the emerging potential of intelligent engineered bacterial delivery systems to drive in situ peptide self-assembly, expanding the boundaries of biomaterials and supporting the development of next-generation smart, responsive, and programmable oral peptide delivery systems.