Engineering extracellular vesicles for inflammatory bowel disease and colitis-associated colorectal cancer: from therapeutic innovation to clinical translation.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic relapsing inflammatory disorder that increases the risk of colitis-associated colorectal cancer (CAC). Despite major advances in biologics and small-molecule therapies, many patients experience primary or secondary treatment failure, adverse effects, and disease recurrence, underscoring the need for more effective, targeted therapeutic strategies. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as promising nanoscale therapeutic platforms owing to their intrinsic biocompatibility, low immunogenicity, cargo-protective lipid bilayer, and natural ability to mediate intercellular communication. Recent advances in EV engineering have further expanded their therapeutic potential through genetic modification of parental cells, cargo loading, surface functionalization, and hybrid biomaterial systems, enabling enhanced targeting, drug delivery, immune modulation, tissue regeneration, and anti-tumor activity. This review summarizes the biological characteristics of EVs and discusses recent progress in engineering strategies aimed at improving their therapeutic efficacy in IBD and CAC. We critically evaluate current preclinical evidence regarding immunomodulation, restoration of intestinal barrier integrity, regulation of gut microbiota, targeted drug delivery, cancer immunotherapy, and inhibition of metastasis. Finally, we discuss the major translational challenges, including manufacturing standardization, quality control, large-scale production, safety evaluation, regulatory considerations, and future perspectives necessary for successful clinical implementation of engineered EV-based therapies.