Edible Plant-Derived Exosomes and microRNA-Like Molecules: A Cross-Kingdom Regulatory Network in Diabetes Immunometabolism

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a chronic immunometabolic disorder driven by persistent inflammation and dysregulated glucose metabolism. Conventional nutrition paradigms, which focus primarily on macro- and micronutrients, fail to account for regulatory bioactive molecules that may influence host gene expression. Emerging evidence highlights edible plant-derived exosome-like nanoparticles (ELNs) as novel carriers of microRNA-like molecules capable of mediating cross-kingdom communication. This review synthesizes current knowledge on the biogenesis, molecular cargo, gastrointestinal stability, and systemic distribution of plant ELNs, emphasizing their role in modulating immunometabolic pathways relevant to diabetes. Preclinical evidence suggests that certain plant ELNs may retain structural integrity during gastrointestinal transit and may be internalized by intestinal cells and gut microbiota, although the efficiency and physiological relevance of these processes in humans remain uncertain. These molecules have been reported to regulate key targets involved in insulin signaling (e.g., IRS/PI3K/AKT), inflammation (e.g., NF-κB, NLRP3 inflammasome), and lipid metabolism. Functionally, plant ELNs may enhance insulin sensitivity, suppress pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and promote macrophage polarization toward anti-inflammatory phenotypes. Additionally, they influence host metabolism indirectly via microbiome-mediated pathways. However, evidence supporting cross-kingdom RNA transfer in humans remains limited, and important questions regarding bioavailability, reproducibility, and physiological relevance are still unresolved. Overall, plant-derived ELNs represent an emerging area of research that expands current understanding of diet-derived gene-regulatory signals. Future integration of multi-omics approaches and artificial intelligence may facilitate the development of hypothesis-driven precision nutrition approaches, pending robust validation in human studies