Diabetes mellitus is an escalating global health challenge, with current therapies primarily focused on symptom management rather than targeting the root causes of the disease. Emerging mRNA and gene therapies offer a new frontier by targeting disease mechanisms at the molecular level. This review explores the mechanistic landscape, delivery systems, and therapeutic outcomes of mRNA and gene-based interventions in diabetes. mRNA therapies, notably delivered via lipid nanoparticles, have demonstrated potential in restoring insulin production, enhancing angiogenesis, and modulating immune responses. mRNA therapy for both type 1 and type 2 diabetes using mRNAs of vascular endothelial growth factor-A, fibroblast growth factor 21, and glucagon-like peptide-1 linked to the IgG4 Fc region has shown immense potential in preclinical models of diabetes. Gene therapy for long-term correction of insulin signaling and pancreatic cell reprogramming is widely administered using viral (adeno-associated virus, lentivirus) vectors; however nonviral methods such as lipid nanoparticles and chitosan-based nanoparticles are being investigated in preclinical stages. CRISPR/Cas9 based genome-editing tools are another emerging therapeutic option for diabetes that correct metabolic defects and protect β cells. Despite these advances, delivery efficiency, immunogenicity, and off-target effects remain key translational hurdles for these therapies. Ongoing clinical trials for diabetes, including vascular endothelial growth factor A mRNA therapy for diabetic wound healing and fibroblast growth factor 21 gene therapy for type 1 diabetes, highlight the promising applications of these technologies. With careful attention to safety and pharmacokinetics, mRNA and gene therapies hold transformative promise as next-generation treatments for diabetes and its complications. SIGNIFICANCE STATEMENT: This review highlights emerging mRNA and gene therapies targeting the root causes of diabetes. By focusing on molecular mechanisms, delivery systems, and clinical advances, the review outlines next-generation strategies for treating diabetes and its complications.
