Advances in cellular and structural engineering of brain organoids for disease modeling: A Comprehensive Review

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Organoid technology has rapidly evolved as a transformative tool for modeling human physiology and disease. Organoids are three-dimensional, stem cell-derived constructs that self-organize to recapitulate key structural and functional features of native organs. Among known organoids, brain organoids have provided unprecedented insights into human neurodevelopment and pathophysiology, overcoming the limitations of traditional two-dimensional cultures and animal models. These models closely mimic the architecture, cellular diversity, and regional specification of the human brain, offering a physiologically relevant platform for mechanistic studies. Therefore, brain organoids have become indispensable for investigating complex neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. This review aims to discuss recent advancements in brain organoid technology, emphasizing innovations in each component of the system: cells, supporting cells, three-dimensional architecture, and microenvironment, particularly in the context of major neurological diseases. Notably, brain organoids provide valuable platforms for understanding molecular mechanisms, identifying therapeutic targets, and evaluating drug responses by preserving patient-specific genetic backgrounds and faithfully recapitulating disease-associated phenotypes. Meanwhile, advances in transcriptomic profiling, vascularization strategies, region-specific induction, and CRISPR/Cas9-based genetic engineering have further enhanced the utility and reproducibility of these techniques. This review summarizes key technological advancements and major findings in brain organoid research, including microenvironmental modulation, high-throughput culture platforms, and integrative analysis tools. We also highlight the associated applications in disease modeling, drug screening, and personalized medicine, while addressing current limitations and ethical considerations. As brain organoid systems continue to mature, through innovations such as assembloids, vascular integration, and patient-derived modeling, these systems offer great promise for bridging the translational gap in neuroscience and neurotherapeutics between bench and bedside. Recent advances in brain organoid technology. Brain organoids are three-dimensional structures derived from stem cells that self-organize to recapitulate key features of human brain tissue. Brain organoids serve as valuable models for studying neurodevelopmental processes, disease mechanisms, and drug screening. Recent progress in organoid research includes innovative approaches such as targeted cell and genetic modifications, improvements in embryoid body (EB) spheroid formation, microenvironment engineering, and the development of advanced culture technologies to enhance organoid complexity and functionality. • Brain organoids facilitate detailed modeling of human neurodevelopment and neurological disorders. • Advancements such as genetic editing and vascularization enhance the complexity and physiological relevance of organoids. • Region-specific brain organoids derived from patient cells enable the creation of personalized, targeted models for neurological research and therapy. • The integration of bioengineering techniques improves the scalability and functional capabilities of brain organoids. • Organoid fusion presents an innovative, multi-organ approach, offering more comprehensive and precise models of neurological diseases.