Enhancing GLP-1 expression via IVT mRNA and fusion protein technology for diabetes therapy.

BACKGROUND: Diabetes is a chronic metabolic disorder with high incidence and prevalence worldwide. This study explores a novel glucagon-like peptide-1-Fc (GLP-1-Fc) mRNA designed to improve diabetes management by inducing stable and persistent production of GLP-1-Fc protein. METHODS: The GLP-1-Fc mRNA was generated using in vitro transcription and fusion protein technology. Protein expression was assessed via western blot and enzyme-linked immunosorbent assay (ELISA) in Human Embryonic Kidney 293T (HEK293T) cells. GLP-1-Fc mRNA and GLP-1-Fc protein (dulaglutide) were administered to C57BL/6J and db/db mice to evaluate protein levels, GLP-1 receptor activity, hypoglycemic effects, and safety using ELISA, lance ultra cAMP assay, blood glucose levels detection, immunofluorescence, and hematoxylin and eosin staining. RESULTS: The designed mRNA fused with the Fc region successfully encoded GLP-1-Fc, showing optimal stability and translation efficiency. The GLP-1-Fc protein levels were significantly higher in the GLP-1-Fc mRNA treatment group than those in the control mice. The GLP-1-Fc mRNA effectively reduced blood glucose levels and increased GLP-1 receptor expression in db/db mice after both single and repeated administrations. Moreover, the GLP-1-Fc mRNA provided prolonged glucose reduction with similar efficacy to GLP-1 protein drug, dulaglutide. Besides, intraperitoneal delivery of GLP-1-Fc mRNA does not induce tissue damage. CONCLUSIONS: Compared to conventional peptide-based therapies, GLP-1-Fc mRNA represents a promising strategy for diabetes treatment by enabling sustained in vivo protein expression, achieving effective glycemic control, and offering a streamlined manufacturing process with reduced production complexity.