Engineering Organoid Platforms for Pathogenesis Research

Emerging and re-emerging infectious diseases ranging from the 1918 H1N1 influenza pandemic to the recent SARS-CoV-2 and monkeypox virus outbreaks continue to pose profound threats to global public health. These crises underscore the critical need for high-fidelity and human-relevant infection models. Organoid technology has emerged as a cornerstone platform for pathogen research by faithfully recapitulating the 3-dimensional architecture and physiological microenvironment of native human tissues in vitro. This review systematically examines the development and structural refinement of organoid-based infection models with an emphasis on evidence-based strategies for stem cell source selection, extracellular matrix optimization, and dynamic culture system engineering. Such advancements enable the robust generation of multi-organ models including respiratory, intestinal, and neural organoids tailored for investigating viral tropism, spatiotemporal infection kinetics, and host immune responses. Furthermore, we evaluate the translational utility of organoids in high-throughput antiviral drug screening and preclinical vaccine assessment. To further enhance physiological relevance and functional fidelity, organoid platforms are being increasingly combined with advanced engineering strategies, including coculture approaches, CRISPR-Cas9-mediated genetic perturbation, engineered microphysiological systems (such as organ-on-a-chip), and 3D bioprinting. These integrated technologies improve biomimicry while expanding experimental controllability and scalability. In addition, we critically examine the major bottlenecks limiting clinical translation and discuss emerging frontiers driven by artificial intelligence and synthetic biology. Through iterative technological refinement and cross-disciplinary convergence, organoids have evolved beyond reductionist in vitro surrogates into physiologically informed and mechanism-driven platforms that advance our understanding of host-pathogen interactions while enhancing global preparedness against emerging pathogens.