Plant-Derived Nanovesicles as a Cross-Kingdom Therapeutic Approach for T2DM and Related Metabolic Disorders: Current Evidence and Future Perspectives.

Type 2 diabetes mellitus (T2DM) is increasingly viewed as a systemic metabolic disorder rather than as an isolated glycemic defect. It is closely linked to obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), sharing mechanisms such as insulin resistance, chronic inflammation, and interorgan crosstalk among the gut, liver, adipose tissue, pancreas, and central nervous system. Plant-derived nanovesicles (PDNVs) are emerging cross-kingdom nanoplatforms with the potential to modulate metabolic and inflammatory signaling. Evidence from T2DM, obesity, and MASLD models suggests that PDNVs can improve metabolic homeostasis by reprogramming metabolism and reducing inflammation. PDNVs may modulate organ axes, particularly gut-liver and gut-brain axes, and potentially adipose-liver and liver-pancreas axes, partly via context- and tissue-dependent regulation of AMPK-, PI3K-AKT-, and SIRT1-related pathways. Strategies such as structural engineering, surface functionalization, and cargo loading optimization may further enhance the stability, bioavailability, and targeting capacity of PDNVs, thereby supporting their application in metabolic diseases.