Extracellular vesicles (EVs) are 30–150 nm membrane-bound vesicles naturally secreted by cells and play important roles in intercellular communication by delivering regulatory molecules such as proteins, lipids, nucleic acids and metabolites to recipient cells. As natural nano-carriers, EVs possess desirable properties such as high biocompatibility, biological barrier permeability, low toxicity, and low immunogenicity, making them potential therapeutic delivery vehicles. EVs derived from specific cells have inherent targeting capacity towards specific cell types, which is yet not satisfactory enough for targeted therapy development and needs to be improved. Surface modifications endow EVs with targeting abilities, significantly improving their therapeutic efficiency. Herein, we first briefly introduce the biogenesis, composition, uptake and function of EVs, and review the cargo loading approaches for EVs. Then, we summarize the recent advances in surface engineering strategies of EVs, focusing on the applications of engineered EVs for targeted therapy. Altogether, EVs hold great promise for targeted delivery of various cargos, and targeted modifications show promising effects on multiple diseases. Graphical Abstract

As a main digestive organ and an important immune organ, the intestine plays a vital role in resisting the invasion of potential pathogens into the body. Intestinal immune dysfunction remains important pathogenesis of inflammatory bowel disease (IBD). In this review, we explained the interactions among symbiotic flora, intestinal epithelial cells, and the immune system, clarified the operating mechanism of the intestinal immune system, and highlighted the immunological pathogenesis of IBD, with a focus on the development of immunotherapy for IBD. In addition, intestinal fibrosis is a significant complication in patients with long-term IBD, and we reviewed the immunological pathogenesis involved in the development of intestinal fibrogenesis and provided novel antifibrotic immunotherapies for IBD.

Plant-derived exosome-like nanoparticles (PDENs) have been paid great attention in the treatment of ulcerative colitis (UC). As a proof of concept, we isolated and identified Portulaca oleracea L-derived exosome-like nanoparticles (PELNs) from edible Portulaca oleracea L, which exhibited desirable nano-size (~ 160 nm) and a negative zeta potential value (-31.4 mV). Oral administration of PELNs effectively suppressed the expressions of pro-inflammatory cytokines (TNF-α, IL-6, IL-12, and IL-1β) and myeloperoxidase (MPO), increased levels of the anti-inflammatory cytokine (IL-10), and alleviated acute colitis in dextran sulfate sodium (DSS)-induced C57 mice and IL-10^−/− mice. Notably, PELNs exhibited excellent stability and safety within the gastrointestinal tract and displayed specific targeting to inflamed sites in the colons of mice. Mechanistically, oral administration of PELNs played a crucial role in maintaining the diversity and balance of gut microbiota. Furthermore, PELNs treatment enhanced Lactobacillus reuteri growth and elevated indole derivative levels, which might activate the aryl-hydrocarbon receptor (AhR) in conventional CD4⁺ T cells. This activation downregulated Zbtb7b expression, leading to the reprogramming of conventional CD4⁺ T cells into double-positive CD4⁺CD8⁺T cells (DP CD4⁺CD8⁺ T cells). In conclusion, our findings highlighted the potential of orally administered PELNs as a novel, natural, and colon-targeted agent, offering a promising therapeutic approach for managing UC. Graphic Schematic illustration of therapeutic effects of oral Portulaca oleracea L -derived natural exosome-like nanoparticles (PELNs) on UC. PELNs treatment enhanced Lactobacillus reuteri growth and elevated indole derivative levels, which activate the aryl-hydrocarbon receptor (AhR) in conventional CD4⁺ T cells leading to downregulate the expression of Zbtb7b, reprogram of conventional CD4⁺ T cells into double-positive CD4⁺CD8⁺T cells (DP CD4⁺CD8⁺ T cells), and decrease the levels of pro-inflammatory cytokines.

The intestinal barrier maintained by various types of columnar epithelial cells, plays a crucial role in regulating the interactions between the intestinal contents (such as the intestinal microbiota), the immune system, and other components. Dysfunction of the intestinal mucosa is a significant pathophysiological mechanism and clinical manifestation of inflammatory bowel disease (IBD). However, current therapies for IBD primarily focus on suppressing inflammation, and no disease-modifying treatments specifically target the epithelial barrier. Given the side effects associated with chronic immunotherapy, effective alternative therapies that promote mucosal healing are highly attractive. In this review, we examined the function of intestinal epithelial barrier function and the mechanisms of behind its disruption in IBD. We illustrated the complex process of intestinal mucosal healing and proposed therapeutic approaches to promote mucosal healing strategies in IBD. These included the application of stem cell transplantation and organ-like tissue engineering approaches to generate new intestinal tissue. Finally, we discussed potential strategies to restore the function of the intestinal barrier as a treatment for IBD.

The organoids represent one of the greatest revolutions in the biomedical field in the past decade. This three-dimensional (3D) micro-organ cultured in vitro has a structure highly similar to that of the tissue and organ. Using the regeneration ability of stem cells, a 3D organ-like structure called intestinal organoids is established, which can mimic the characteristics of real intestinal organs, including morphology, function, and personalized response to specific stimuli. Here, we discuss current stem cell-based organ-like 3D intestinal models, including understanding the molecular pathophysiology, high-throughput screening drugs, drug efficacy testing, toxicological evaluation, and organ-based regeneration of inflammatory bowel disease (IBD). We summarize the advances and limitations of the state-of-the-art reconstruction platforms for intestinal organoids. The challenges, advantages, and prospects of intestinal organs as an in vitro model system for precision medicine are also discussed.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic autoimmune disorder characterized by inflammation.