03096nas a2200289   4500000000100000008004100001260001500042653002000057653004100077653003100118653002100149653002000170100002200190700002700212700001800239700002200257700001900279700002200298700002700320700001600347245012800363856005000491300000900541490000600550520223600556022001402792       2025                            d  c2025-12-0810abrain organoids10ahuman pluripotent stem cells (hPSCs)10aNeurodegenerative Diseases10aorgans-on-a-chip10avascularization1 aSoupayan Banerjee1 aPranathi Mirale Chandu1 aMeghna Sarkar1 aTanveen Kaur Soni1 aMadhumita Saha1 aFathah Muhammad L1 aBhaskarjyaa Chatterjee1 aUddalak Das00aEngineering brain organoids and organ-on-chip systems for modeling neurodevelopmental and neurodegenerative pathophysiology  uhttps://doi.org/10.1080/01616412.2025.2600434  a1-180 v03 aNeurodevelopmental and neurodegenerative disorders arise from complex disruptions in brain structure and function, many originating during early development. However, conventional in vitro and animal models often fail to capture the cellular diversity, temporal dynamics, and architectural complexity of the human brain. This review aims to synthesize recent advances in stem-cell–derived in vitro platforms, specifically brain organoids, assembloids, and organ-on-chip technologies, and evaluate how these systems are reshaping research on Alzheimer’s and Parkinson’s diseases by enabling more human-relevant modeling. We surveyed recent literature focusing on region-specific and vascularized organoids, integrated neuronal subtype models, and microfluidic organ-on-chip systems. Particular attention was given to studies demonstrating increased physiological relevance, enhanced modeling of disease-specific phenotypes, and expanding utility in translational research, therapeutic screening, and drug discovery pipelines. Innovations in organoid engineering have enabled more faithful recapitulation of human brain development and degeneration. These platforms have advanced understanding of amyloid aggregation, neuroinflammatory processes, dopaminergic neuron vulnerability, and gut–brain axis contributions. The incorporation of vascular structures, improved microfluidic control, and assembly of multi-region neuronal circuits have strengthened functional readouts and boosted mechanistic insight. Collectively, these developments are accelerating preclinical therapeutic testing and enabling more predictive disease modeling. Compared to prior reviews, this article uniquely integrates developmental and degenerative perspectives while evaluating emerging strategies that increase reproducibility and translational accuracy. Persistent limitations, including incomplete vascularization, cellular stress responses, and batch-to-batch variability, underscore the need for improved standardization and incorporation of immune components. Future directions that merge vascular, immune, and circuit-level complexity promise to advance organoid-based neuroscience toward personalized modeling and therapeutic application.  a0161-6412