Abstract

Obesity-induced type 2 diabetes (T2D) emerges from sustained nutrient surplus, low-grade inflammation, and 
interorgan crosstalk that locks adipose tissue, liver, skeletal muscle, and pancreatic islets into insulin-resistant 
states. Exosomes - 30–150 nm extracellular vesicles are central messengers in this network, shuttling 
microRNAs, proteins, and lipids that remodel recipient cell programs. Native exosomes show therapeutic 
promise but face practical barriers: heterogeneous composition, low yield, batch variability, and concerns about 
immunogenicity and scalability. Exosome-mimicking nanoparticles (EMNs) seek to capture exosomal 
advantages like biophysical architecture, ligand-guided tropism, and efficient cellular entry while enabling 
reproducible, cGMP-ready manufacture. Built from lipids, polymers, or membrane-cloaked hybrids, EMNs can 
be engineered for organ selectivity and loaded with small molecules, peptides, RNAs, and genome editors to 
recalibrate insulin signaling, mitochondrial function, and inflammatory tone. Rational design uses exosomal 
lipidomics, integrin-mimetic motifs, and glycoconjugates to improve uptake and endosomal escape, while tuning 
size, stiffness, and surface chemistry to navigate the reticuloendothelial system characteristic of obesity. 
Preclinical studies in diet-induced models demonstrate improvements in hepatic steatosis, adipose inflammation, 
skeletal muscle oxidative metabolism, and β-cell resilience, often at lower doses than free drugs. Translation 
now hinges on standardized potency assays, biodistribution profiling in metabolically diseased hosts, long-term 
safety, and industrial control of critical quality attributes. This review integrates pathophysiologic rationale, 
design rules, targeting strategies, efficacy readouts, and manufacturing considerations to chart a practical route 
for first-in-human evaluation of EMNs in obesity-driven T2D.