Engineering single-dose plasmid DNA for sustained in vivo delivery of designer incretins.

Incretin mimetic drugs have transformed the treatment of obesity and type 2 diabetes; however, production and patient compliance challenges remain. Plasmid DNA has recently demonstrated the ability to deliver functional monoclonal antibodies for over a year in human patients. We generated plasmid-encoded long-acting incretins (pLincretins) by fusing cleavage-resistant glucagon-like peptide-1 and gastric inhibitory polypeptide analogues with IgG heavy chain (Fc) components. Plasmids were delivered to diet-induced obese mice using a clinically validated electroporation device. A single administration drove sustained expression, supporting durable reductions in body weight, food intake, and blood glucose. Building on this framework, we used AI-guided protein modeling and a synthetic consensus approach to design a dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic polypeptide receptor agonist [plasmid-encoded synthetic consensus incretin (pSynCretin)]. pSynCretin demonstrated enhanced GLP-1R avidity and induced potent weight loss in vivo. These findings establish DNA-launched incretin mimetics as a potential therapeutic tool that combines the potency of next-generation metabolic hormones with the durability, safety, and translational feasibility of plasmid delivery.