Three-Dimensional Organoids in Metal Biology: Metabolism, Toxicity Assessment, and Therapeutic Applications

Abstract

Metals have dual biological roles. Essential metals, including magnesium, zinc, and copper, are required for physiological functions within narrow homeostatic windows, whereas non-essential metals such as cadmium may exert toxic effects even at low exposure levels. Chemical form—ion, complex, or nanoparticle—further influences biological fate. However, current mechanistic understanding remains largely based on two-dimensional (2D) monolayers and animal models, both of which incompletely capture the tissue architecture and cell–cell crosstalk that govern metal behavior in vivo. Three-dimensional (3D) organoid technology has emerged as a promising approach to address this gap. This review synthesizes how intestinal, brain, kidney, liver, breast, cardiac, and tumor organoids have been used to assess metal-induced morphogenesis, metabolic reprogramming, toxicity, and therapeutic responses. We first summarize conventional findings related to metabolism, toxicity, and detoxification, and then highlight organoid-specific insights: low-dose silver nanoparticles prolong the cell cycle by impairing ciliogenesis, whereas high doses trigger apoptosis; intestinal organoids link copper handling to lipid uptake; prostate organoids reveal miR-183-regulated zinc homeostasis; and engineered nanozymes selectively scavenge reactive oxygen species in inflamed microenvironments. Critical gaps remain: most platforms lack vasculature, immune components, and systemic metabolic clearance; chronic low-dose studies are rare; and genetically diverse biobanks remain limited. Addressing these gaps is essential for transforming organoids into reliable predictive platforms for metal toxicology and drug development.