Advanced microbial therapeutics (AMTs) for enhanced in situ delivery of therapeutic peptides and proteins

Oral administration of drugs is the most preferred method due to its convenience and high patient compliance. However, oral delivery of therapeutic peptides and proteins remains a significant challenge due to poor absorption and low bioavailability caused by the harsh gastrointestinal environment and epithelial barriers. Advanced Microbial Therapeutics (AMTs) leverage genetically engineered microorganisms to produce and deliver therapeutic molecules directly within the gastrointestinal tract, facilitating efficient local delivery. To further promote peptide absorption into systemic circulation using AMTs, our research integrates strategies such as cell-penetrating peptides (CPPs) and neonatal Fc receptor (FcRn) targeting. We identified CPPs that effectively enhance epithelial permeability and demonstrated that probiotic strains like Saccharomyces boulardii can be engineered to produce these peptides in situ, significantly improving intestinal absorption of a macromolecule in mice. Additionally, we engineered Escherichia coli Nissle 1917 (EcN) to produce Fibroblast Growth Factor 21 (FGF21) fused with FcRn binders to facilitate FcRn-mediated transcytosis, thereby increasing its absorption in vitro. To further enhance the absorption capabilities of peptides and proteins, we investigated fusion proteins combining therapeutic peptides with an engineered albumin variant designed to improve FcRn binding and transepithelial transport. This albumin fusion strategy is poised for future integration into AMTs to facilitate efficient systemic delivery of therapeutic peptides and proteins. Overall, integration of oral peptide delivery approaches in the context of AMTs showcase the potential for non-invasive and effective systemic delivery of peptide and protein therapeutics, establishing AMTs as a transformative strategy in oral drug delivery.