Extracellular vesicles for diabetes and its complications: Harnessing mammalian and plant sources from direct interventions to engineered applications.

Current therapies for diabetes mellitus, a highly prevalent chronic metabolic disorder, rarely achieve etiological intervention and are limited by poor patient compliance and significant side effects. Extracellular vesicles (EVs), nanoscale carriers of intercellular communication, offer a promising therapeutic alternative due to their high biocompatibility, low immunogenicity, and inherent capacity for delivering biomolecules to specific targets. This review systematically synthesizes recent progress in EV-based strategies for diabetes. First, we examine how mammalian-derived EVs (such as from mesenchymal stem cells and immune cells) directly protect and restore pancreatic β-cells, restore immune tolerance, and ameliorate systemic insulin resistance. Second, we highlight the emerging potential of plant-derived EVs, which allow for oral administration and modulate metabolism via gut-organ axes. We further discuss the engineering of EVs into targeted drug delivery systems, with a focus on breakthroughs in oral insulin delivery and their applications in treating diabetic complications, including nephropathy, chronic wounds, and liver-brain axis-related disorders. Finally, we outline the key challenges of standardization, scalable production, and clinical translation, proposing a roadmap for future research. This comprehensive analysis underscores the potential of EVs to provide transformative strategies for diabetes management through multifaceted mechanisms and innovative engineering strategies.