Implement enhanced artificial “enteroendocrine L cells” via oral administration for effective treatment of type 2 diabetes

<h2>Summary</h2> "Enteroendocrine L cells," responsible for secreting glucagon-like peptide-1 (GLP-1) to regulate blood glucose levels, are adversely affected when type 2 diabetes (T2D) develops. Here, we developed enhanced artificial enteroendocrine L cells (EcN-GLP-1@Fe-TA-Pe@CLGN) for T2D treatment via oral administration by genetically engineering probiotics to continuously secrete GLP-1 (EcN-GLP-1), on which an Fe³⁺-polyphenol-based adhesive layer (Fe-TA) hosting pelargonidin (Pe)-based intestinal permeation enhancers and a prebiotic-based covalent crosslinking coating (CLGN) were successively formed. Shielded by CLGN, EcN-GLP-1@Fe-TA-Pe@CLGN withstood gastrointestinal stresses to reach the intestines. After CLGN was metabolized by gut microbiota into short-chain fatty acids (SCFAs), the underlying Fe-TA was exposed to assist colonization and initiate Pe release for intestinal permeability improvement. Consequently, GLP-1 secreted from EcN-GLP-1 and SCFAs achieved high bioavailability to synergistically combat T2D, leading to hyperglycemia/hyperlipidemia relief, major organs repair, and improved ecology of gut microbiota. This strategy provides insights into reforming microorganisms to mimic and improve cells' features for disease treatment.