Engineered extracellular vesicle therapies for regulating gut immunity: advances and challenges

The intestine is the largest immune organ and plays a critical role in regulating local and systemic tissue homeostasis, while disruption of gut immunity can drive an array of diverse diseases both within and beyond the gut.However, current clinical therapeutics (mainly anti-inflammatory drugs) display limited efficacy in restoring gut immune homeostasis and often cause severe side effects.Therefore, new therapeutic strategies are needed to regulate gut immunity for disease treatment.In recent years, extracellular vesicle (EV)-based therapies have emerged as promising nanomedicines for treating gut immune disorder-related diseases by mediating multilayered signaling networks composed of immune cells, resident cells, and the gut microbiota.EVs from diverse sources (e.g., mammalian cells, food, plants and microbiota) may regulate gut immunity by modulating the phenotypes of diverse immune cells (e.g., macrophages, dendritic cells, and T cells), gut barrier integrity, and host-microbiota communication, with therapeutic effects reported mainly in preclinical models of gut immune disorders, such as inflammatory bowel disease, metabolic diseases, graft-versus-host disease, allergies, and colorectal cancer.EVs can be further engineered via cargo loading or surface modification to enhance their targeting ability and specific therapeutic efficacy.Overall, preclinical findings support further investigations of EV-based gut immunotherapy, but the clinical efficacy and long-term safety remain to be established.