Tea ExtracellularVesicle-Derived MicroRNAs Contributeto Alleviate Intestinal Inflammation by Reprogramming Macrophages

The clinical use of conventional medications for inflammatory bowel disease (IBD) is often limited by significant side effects. The extracellular vesicles derived from plant-based diets have shown promise in mitigating disease. Here, we discovered that natural extracellular vesicles from tea (TEVs) can achieve an appropriate transition from proinflammatory (M1) to anti-inflammatory (M2) macrophages and inhibit inflammation response both in vitro and in vivo. More importantly, the therapeutic effects of TEVs were at least partially attributed to RNA in a DSS-induced colitis model. Small RNA sequencing revealed a distinct enrichment of miRNAs in TEVs, with target genes primarily linked to IBD. TEVs were absorbed by macrophages in a time-dependent manner, carrying miRNAs that modulate gene expression within host cells. Notably, TEV-derived osa-miR166d-5p and gma-miR396a-3p were shown to enhance M2 macrophage polarization and reduce inflammation in vitro. Mechanistically, the osa-miR166d-5p- and gma-miR396a-3p-mediated targeting of the 3′-UTRs of AKT1 and IKBKB decreased NF-κB levels. Overall, we demonstrated that TEVs can ameliorate mouse colitis by reprogramming macrophage polarization and contain a unique miRNA repertoire, including osa-miR166d-5p and gma-miR396a-3p, with a novel function of alleviating intestinal inflammation.