Gene-modified MSC-Exos show therapeutic potential for insulin resistance by targeting mitochondrial crosstalk and miRNA regulation

Insulin resistance (IR) is a central pathology driving type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and other cardiometabolic disorders. Current treatments often focus on symptomatic relief rather than addressing the underlying cellular dysfunction, particularly impaired insulin signaling and mitochondrial health. Mesenchymal stem cell-derived exosomes (MSC-Exos) offer a promising cell-free therapeutic alternative due to their ability to deliver a diverse cargo of miRNAs, proteins, and mitochondrial regulators, potentially restoring the crucial IRS1/PI3K/Akt/GLUT4 axis and protecting pancreatic β-cells.

This comprehensive review synthesizes current research on the therapeutic potential of gene-modified MSC-Exos for insulin resistance. It explores how genetic engineering strategies can enhance MSC-Exo efficacy by modulating specific miRNA expression and Sirtuin levels. The review focuses on the mechanisms by which these modified exosomes can restore insulin signaling, protect β-cells, alleviate endoplasmic reticulum (ER) stress, and rescue mitochondrial function, including mitophagy and respiration. It also discusses the critical challenges for clinical translation, such as scalable good manufacturing practice (GMP) production, long-term safety, and regulatory pathways for advanced therapy medicinal products.

Gene-modified MSC-Exos demonstrate significant potential to overcome limitations of conventional therapies for insulin resistance by directly targeting cellular dysfunction. The review highlights how these engineered vesicles can deliver specific miRNAs and proteins to reactivate the IRS1/PI3K/Akt/GLUT4 pathway, which is essential for glucose uptake and metabolism. Beyond this, MSC-Exos are shown to protect pancreatic β-cells from damage, reduce cellular stress by alleviating endoplasmic reticulum stress, and crucially, rescue mitochondrial mitophagy and respiration to improve cellular energy dynamics. Genetic engineering strategies amplify this therapeutic efficacy:

Improving the expression of miR-21, miR-3075, or Sirtuin-3, and silencing miR-29b-3p are identified as key modifications that enhance the exosomes' ability to modulate insulin signaling and mitochondrial health, shifting treatment paradigms towards precision disease-modifying therapy.