Construction of Vascularized Intestinal Organoids Based on Scaffolds, Hydrogels, and 3D Printing Technologies and Their Applications in Drug Delivery

Abstract

Abstract Intestinal organoids can recapitulate key features of the native intestinal epithelium in vitro, including its three-dimensional architecture, cellular diversity, and certain physiological functions. As a result, they have emerged as valuable tools for investigating intestinal development, disease mechanisms, and drug discovery. Nevertheless, conventional intestinal organoids are largely generated through self-organization and often suffer from limited structural controllability, the absence of functional vascular networks, incomplete immune microenvironments, and restricted long-term culture stability. These limitations hinder their ability to faithfully reproduce the complex processes of nutrient transport, inflammatory regulation, and drug absorption observed in vivo. Recent advances in biomaterials, hydrogel systems, functional nanomaterials, three-dimensional (3D) bioprinting, and microfluidic technologies have opened new opportunities for the development of vascularized, immune-competent, and engineered intestinal organoids. By tailoring the mechanical properties, pore architecture, degradation characteristics, and bioactive modifications of hydrogels, researchers can create a more physiologically relevant three-dimensional niche for intestinal epithelial cells, endothelial cells, and immune cells. In addition, the incorporation of immune cells and microbiota-related components provides opportunities to investigate epithelial–immune interactions, inflammatory regulation, and host–microbiota crosstalk in a more physiologically relevant microenvironment. In combination with 3D bioprinting, biomimetic crypt–villus structures, vascular channels, and spatially controlled signaling gradients can be fabricated with high precision. Furthermore, the incorporation of perfusable vascular networks and microfluidic platforms improves oxygen and nutrient delivery, thereby enhancing the simulation of drug uptake, trans-epithelial transport, and immune cell trafficking. This review summarizes recent progress in the fundamental construction of intestinal organoids, vascularization strategies, immune microenvironment regulation, scaffold and hydrogel materials, the enhancement mechanisms of nanomaterials and rare-earth-based nanomaterials, 3D bioprinting approaches, and applications in drug delivery. Current challenges and future perspectives are also discussed. Vascularized intestinal organoids are expected to serve as a promising in vitro platform bridging tissue engineering, disease modeling, drug delivery research, and precision medicine.