Human Brain Organoid-Enabling Discoveries Reach the Clinic: A Translational Inflection Point.

Brain organoids in Parkinson's disease drug development: Human-specific models for translational discovery.

Parkinson's disease (PD) poses a major unmet therapeutic challenge, with most drug candidates failing in clinical translation despite promising animal model data. Human induced pluripotent stem cell-derived midbrain organoids recapitulate key PD pathological hallmarks - including dopaminergic neuron loss, α-synuclein aggregation, and neuroinflammation - in a genetically defined, human-specific context. This review summarizes drug screening studies in midbrain organoids across genetic, toxin-based, and α-synuclein preformed fibril models. We highlight therapeutic interventions that rescue PD phenotypes, compare organoid and animal model systems, and discuss the personalized medicine potential of patient-derived organoids. We also critically assess current limitations and outline how artificial intelligence integration and assembloid platforms are advancing organoid-based drug discovery towards regulatory acceptance.

Emerging Role of Human Organoids in Drug Discovery and Development: Current Advances and Challenges

Modeling Epilepsies with Human Brain Organoids: Recent Advances and Ongoing Challenges

Recent advances and ongoing challenges of human cortical organoid models of genetic and acquired epilepsies hold promise for advancing mechanistic understanding of epilepsy and enabling the development of more precise therapeutic strategies.

Brain Organoids as Emerging Platforms for Modeling CNS Infections: Neuropathogenesis, Therapeutic Discovery, and Drug Delivery.

Neurotropic viruses remain a persistent global health challenge, and the mechanisms by which they damage the human brain are not yet fully understood. Animal models are often limited by human-specific aspects of CNS biology, whereas two-dimensional (2D) cell cultures cannot recapitulate the complex three-dimensional (3D) cellular interactions that occur during viral infection of the brain. Over the past decade, brain organoids derived from human stem cells have emerged as physiologically relevant models that address these limitations. These 3D cultures self-assemble into structures containing neurons, astrocytes, and progenitor cells arranged in patterns that resemble early brain development. This review examines the application of brain organoids to the study of infections caused by Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), herpes simplex virus (HSV), and human immunodeficiency virus type 1 (HIV-1). Studies were screened from PubMed and shortlisted based on their relevance to organoid-based CNS infection modeling, antiviral drug screening, CNS-targeted drug delivery, and neuroinflammation. Organoid-based antiviral screening has identified promising compounds from libraries containing more than 1,000 candidates. Drug delivery strategies are also discussed, with particular emphasis on nanoparticles, polymer-based carriers, and extracellular vesicles (EVs) evaluated in organoid and spheroid models for their ability to cross the blood-brain barrier (BBB) and deliver therapeutic cargo to neural cells. The roles of damage-associated and pathogen-associated molecular patterns (DAMPs and PAMPs) in neuroinflammation, complement evasion, and chronic post-infection damage, including long COVID, are also examined. Current limitations, including the lack of functional vasculature, incomplete BBB components, and reproducibility challenges, are discussed. Despite these limitations, CNS organoids bridge the gap between basic research and clinical application, advancing the development of effective therapies for viral infections of the brain.

Engineering Neural Organoids: Technological Advances and Translational Frontiers.

The goal is not to replicate the brain in miniature, but to reconstruct its organizing principles in an experimentally accessible system, offering new insights into human neural complexity while advancing neuroscience and medicine.

Brain Organoids in Alzheimer’s and Parkinson’s Disease: Clinical Applications and Translational Perspectives