From Organoids to Organ-on-Chip: Advancing Human-Relevant Models for Viral Pathogenesis and Antiviral Drug Discovery

Abstract

Highlights What are the main findings? Organoids and organ-on-chip models provide more physiologically relevant systems for studying viral tropism, replication, dissemination, tissue injury, immune responses, and virus–host interactions than conventional 2D cultures. Brain, intestinal, and respiratory organoids have revealed tissue-specific mechanisms of viral infection, including HSV-1 neuroinvasion and neuroinflammation, Zika and dengue virus-induced neuronal injury, norovirus infection in intestinal models, and SARS-CoV-2 infection and pathogenesis in respiratory models. Incorporating immune and stromal cells, vascular components, microfluidics, and real-time monitoring enable these models to better capture the dynamic interactions between viruses, tissues, and host responses. The field is moving toward increasingly integrated human-relevant platforms that can model infection, inflammation, and tissue injury together, creating more predictive systems for antiviral discovery, therapeutic evaluation, and vaccine development. What is the implication of the main finding? Organoid and organ-on-chip platforms can bridge the gap between conventional cell culture and human disease by reproducing key features of tissue organization, local host responses, and differences in viral susceptibility and treatment response. They also provide human-relevant systems for assessing drug efficacy, toxicity, and therapeutic windows. Advances in maturation, standardization, reproducibility, scalability, biosafety, and validation could enable these models to improve drug candidate selection, toxicity assessment, and dose optimization, making preclinical development more predictive and accelerating the development of safer, more effective antiviral therapies. Abstract Organoid and organ-on-chip technologies are rapidly evolving platforms for viral research that integrate stem cell biology, tissue engineering, and microfluidics to recapitulate key structural, mechanical, biochemical, and cellular features of human and animal physiology. By incorporating multicellular organoids into perfused microfluidic systems, these models can provide complex, dynamic, and physiologically relevant micro-environments for investigating virus–host interactions that are difficult to capture in conventional two-dimensional cultures and static organoids. Controlled flow, shear stress, extracellular matrix organization, tissue–tissue interfaces, and multicellular signaling enable mechanistic investigation of viral infectivity, dissemination, tissue injury and immune activation. Integration of real-time imaging and biosensors further permits longitudinal monitoring of viral replication, host responses, and tissue integrity, expanding the potential of these platforms for antiviral drug discovery. Recent organoid-on-chip studies using brain, skin, vaginal, respiratory, and intestinal models have demonstrated how tissue architecture, mechanical forces, glycocalyx dynamics, and immune–stromal interactions influence viral tropism and pathogenesis. In this review, we provide a mechanistic and translational overview of organoid and organ-on-chip technologies for studying viral infections, with particular emphasis on models of herpes simplex virus (HSV)-mediated disease. We further examine advances in immune integration, multi-organ systems, biosensing, and computational approaches that are expanding the complexity and predictive potential of these models. Importantly, patient-derived organoids and organ-on-chip platforms can capture interindividual differences in viral susceptibility, host responses, and therapeutic efficacy, providing pharmaceutical research with more precise, patient-relevant data to support drug prioritization and precision antiviral medicine. Finally, we discuss key barriers to broader adoption, including organoid maturation, biological and technical variability, reproducibility, scalability, biosafety, cost, standardization, and regulatory validation. Collectively, these advances position organoid and organ-on-chip technologies as powerful human-relevant models that bridge reductionist in vitro systems and human disease, while continued optimization, standardization, and validation will be essential to realize their full potential for mechanistically informed antiviral discovery, therapeutic development, and precision medicine.