Organoid–microglia system for modeling the immune microenvironment of the brain and retina

Glial cells play a critical role in neural development, function, and immune regulation, with microglia serving as the principal immune cells of the central nervous system and retina. Although microglia are central to neuroinflammation and disease progression, progress in understanding human microglial biology has been limited by the lack of physiologically relevant in vitro models. Stem cell–derived brain and retinal organoids provide three-dimensional systems that recapitulate human tissue architecture and developmental trajectories, offering new opportunities to study neuroimmune interactions. This review summarizes strategies for integrating microglia into neural organoids through co-differentiation and transplantation, and outlines methodologies for establishing humanized immune microenvironments and assessing microglial maturation, migration, phagocytic function, and inflammatory activation. We highlight applications of organoid–microglia models in neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder, Alzheimer’s disease, and retinal diseases, as well as their potential in drug screening and microglia-targeted interventions. Additionally, emerging technologies—such as organ-on-a-chip platforms, spatial transcriptomics, and multi-omics analyses—are enhancing the physiological relevance and analytical power of these systems. Overall, organoid–microglia platforms bridge a critical gap between conventional cell culture and in vivo models, enabling deeper insights into neuroimmune interactions and accelerating the development of precise immunomodulatory therapies.