MicroRNA‐Enriched Plant‐Derived Exosomes Alleviate Colitis by Modulating Systemic Immunity, Metabolic Homeostasis, and Gut Microbiota

Abstract Ulcerative colitis (UC) is a condition with complex immune dysregulation and chronic intestinal inflammation. Currently, there are still a lack of natural and low‐toxicity therapeutic approaches for UC. Emerging research has underscored the potential of plant‐derived exosomes for UC treatment. In this study, it is found that Centella Asiatica‐derived exosomes (CAEs) have anti‐colitis effects. CAEs selectively accumulate in inflamed colons, enabling targeted delivery of RNA cargos. MicroRNA (miRNA)‐enriched CAEs not only mitigate inflammation but also facilitate the reconstitution of a balanced gut microbiota, characterized by a deceased abundance of pathogenic bacteria (e.g., Salmonella enterica ), as well as regulating 880 serum metabolites. Furthermore, the results indicate the remarkable impact of specific miRNAs from CAEs, such as aof‐miR396b and fve‐miR396c‐3p , on Peak1 target. CAEs attenuate inflammatory responses and enhance the functions of immune cells in the intestinal milieu. Importantly, the safety profile of CAEs is exemplary, with no discernible adverse effects observed in both in vitro and in vivo assays. This study posits plant‐derived exosomes as a potent, targeted, and safe therapeutic modality for UC, representing an alternative to conventional treatments by leveraging the inherent bioactive properties of botanically derived nanovesicles and the cross‐kingdom regulatory potential of plant‐derived miRNAs on mammalian genes.