Human organoids and organ-on-chip systems for AI-guided therapeutic discovery against emerging and re-emerging infections

Abstract

Emerging and re-emerging infections expose a persistent mismatch between the speed of pathogen evolution and the pace of therapeutic development. Conventional two-dimensional cultures are scalable but poorly reproduce tissue architecture, whereas animal models may not capture human-specific tropism, immunity, pharmacokinetics, or toxicity. Human organoids and organ-on-chip systems offer complementary solutions by combining organ-specific human cells with three-dimensional architecture, barrier function, perfusion, mechanical forces, and, increasingly, immune and microbial components. This review evaluates their use in antiviral, antibacterial, antiparasitic, and antifungal pharmacology, with emphasis on drug repurposing, host-directed therapy, RNA and nanomedicine approaches, pharmacokinetic-pharmacodynamic assessment, and tissue-specific safety. We further examine how artificial intelligence, high-content imaging, multi-omics, and computational screening can convert these models into iterative discovery platforms that prioritize targets, compounds, combinations, and biomarkers. Current limitations include incomplete immune and vascular complexity, developmental immaturity, matrix and protocol variability, high cost, biosafety constraints, and limited prospective clinical validation. We propose a pandemic-ready pipeline in which pathogen sequencing and AI-based prioritization are followed by organoid and chip validation, mechanistic omics, multi-organ exposure and toxicity testing, and biomarker-guided clinical translation. Used as complementary rather than universal replacement models, these technologies could reduce false-positive leads, improve dose relevance, and accelerate development of therapeutics that control pathogens while preserving human tissue function.