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

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.