Hany E Marei, Anwarul Hasan
One of the major challenges in neuroscience is understanding how the human brain develops into a highly organized and functionally integrated organ, because many developmental processes cannot be investigated directly in humans and are not fully recapitulated in animal models. Brain organoids derived from human pluripotent stem cells have emerged as powerful three-dimensional (3D) experimental models that recapitulate key features of human neurodevelopment, including regional patterning, cellular diversification, and neural circuit assembly. Recent advances in long-term organoid culture, organoid bioengineering, vascularization, assembloid technology, transplantation, multi-omics, and artificial intelligence have substantially expanded the applications of brain organoids to investigate human neurodevelopment, model neurological disorders, support drug discovery, and advance therapeutic development. Integration of single-cell and spatial multi-omics with computational approaches has enabled robust molecular benchmarking, assessment of developmental fidelity, and evaluation of organoid reproducibility, facilitating direct comparison with primary human fetal brain tissue. However, current organoid systems remain limited owing to incomplete cellular and tissue complexity, inter-organoid variability, limited vascularization, limited functional maturation, and incomplete physiological integration. Continued advances in tissue engineering, computational biology, and standardized differentiation protocols are expected to enhance the biological fidelity and translational utility of brain organoids for basic and translational neuroscience, as well as mechanistic and translational research.