Engineered Vascularization: Neurovascular Niche Remodeling Enables Biomimetic Brain Organoids for Central Nervous System Research

Abstract Preclinical central nervous system (CNS) disease models face a persistent translational gap arising from interspecies differences and limited representation of the human neurovascular microenvironment. Human induced pluripotent stem cell-derived brain organoids provide a human-relevant platform for modeling brain development and disease, but limited vascularization restricts tissue growth, maturation, and neurovascular function. Engineering approaches, including genetic engineering, biomaterials, 3D bioprinting, and organ-on-a-chip technologies, enable greater control over vascular specification, spatial organization, extracellular matrix properties, and perfusion, facilitating more controlled remodeling of the neurovascular niche. This Review summarizes recent advances in engineered vascularization of brain organoids, focusing on engineering strategies, biological outcomes, and applications in neurodevelopmental research, CNS disease modeling, and preclinical drug screening. Particular emphasis is placed on evaluating vascularization using complementary evidence rather than individual vascular markers. Based on quantitative data from 13 published studies, we propose the Multidimensional Quality Assessment Framework for Vascularized Brain Organoids (MQAF-VBO) and highlight relationships between engineering parameters and biological outcomes. Emerging opportunities in nanoengineered biomaterials, programmable platforms, spatial profiling, integrated biosensing, and adaptive bioelectronic systems are also discussed. Collectively, these advances may facilitate the development of more reproducible and physiologically relevant vascularized brain organoids for CNS disease modeling and preclinical drug evaluation.