Abstract

Inflammatory bowel disease (IBD) and its progression to colitis-associated colorectal cancer (CAC) pose significant clinical challenges due to their complex pathogenesis and limited therapeutic options. Plant-derived extracellular vesicle-like particles (PEVLPs) have emerged as promising candidates for targeted therapy, owing to their biocompatibility and intrinsic bioactivity. Here, we isolated and characterized Portulaca oleracea L.-derived extracellular vesicle-like particles (PO-EVLPs) and demonstrated their preferential accumulation in the colon of mouse models through systematic biodistribution studies. Mechanistically, PO-EVLPs exert therapeutic effects via the delivery of miRNAs. Specifically, the enriched miR159-y suppresses TGF- β receptor expression, thereby promoting the expansion of group 3 innate lymphoid cells (ILC3s) in colitic tissues. Furthermore, during the transition from chronic inflammation to carcinogenesis, miR159-y-mediated inhibition of TGF- β receptors prevents TGF- β -driven differentiation of NK cells into ILC1s and the conversion of ILC3s into regulatory innate lymphoid cells (ILCregs), thereby impeding CAC progression. In vivo studies also indicated a favorable safety profile. These findings establish PEVLPs as a multifunctional therapeutic platform that simultaneously targets inflammatory pathways and neoplastic transformation, offering a novel strategy for managing IBD and CAC by precisely modulating mucosal immunity.