ArticleTrends in biotechnology2026
Engineering single-dose plasmid DNA for sustained in vivo delivery of designer incretins.
Article in Trends in biotechnology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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