Therapeutic Potential of Gene Modified MSC-Exos in Insulin Resistance: Mitochondrial Crosstalk and miRNA Regulation.

Insulin resistance (IR) is the key driver of type 2 diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and cardiometabolic disorders. Mesenchymal stem cell-derived exosomes (MSC-Exos) as a potent cell-free alternative can deliver miRNAs, proteins, and mitochondrial regulators to reactivate the IRS1/PI3K/Akt/GLUT4 axis. Beyond restoring insulin signalling, these vesicles can protect β-cells, alleviate endoplasmic reticulum stress, rescue mitochondrial mitophagy and respiration. The genetic engineering strategies including improving the expression of miR-21, miR-3075, or Sirtuin-3, and silencing miR-29b-3p amplify the therapeutic efficacy. However, scalable good manufacturing practice production, long-term safety of modified products, and advanced therapy medicinal product regulation are still needed to overcome. This review will introduce the potential of gene-modified MSC-Exos and miRNAs targeting insulin signalling and mitochondrial rescue, which have shown a shift from symptomatic relief to precision disease-modifying therapy for IR.