Abstract

Obesity-driven type 2 diabetes is increasingly understood as a disease of dysregulated inter-organ 
communication rather than isolated defects in single tissues. Exosomes and related extracellular vesicles (EVs) 
are key mediators of this crosstalk, transporting lipids, proteins and nucleic acids between adipose tissue, liver, 
skeletal muscle, pancreas and immune cells. In obesity, the cargo and secretion patterns of endogenous exosomes 
are profoundly altered, contributing to insulin resistance, metaflammation, and β-cell dysfunction. Exosome
mimetic nanovesicles (EMNVs), like synthetic or bioengineered vesicles that replicate key structural and 
functional features of natural exosomes, have emerged as powerful tools to probe and therapeutically modulate 
these communication pathways. Produced by top-down cell membrane fragmentation or bottom-up assembly 
from defined lipids and proteins, EMNVs can be loaded with drugs, RNAs or proteins and tailored for specific 
tissue tropism, while avoiding some manufacturing and scalability limitations of native exosomes. This review 
discusses the role of EV-mediated inter-organ communication in obesity-driven diabetes, the rationale for using 
EMNVs to interrogate and rewire these networks, and key design principles of exosome-mimetic systems. It 
then examines how EMNVs can be used to modulate adipose–liver–muscle–β-cell crosstalk, summarizes 
preclinical evidence, and highlights translational challenges, including heterogeneity, safety, and regulatory 
classification. Finally, it outlines future directions, including precision EMNVs carrying cargo that reprogram 
pathogenic signaling axes, integration with metabolic drugs, and potential use as “message decoys” to buffer 
harmful obesity-associated vesicle signals.