The multiverse of zebrafish within the nanoworld

The zebrafish (Danio rerio) has evolved into a strategic, high-throughput platform, bridging the critical gap between in vitro assays and costly mammalian studies in nanomedicine development. This is underscored by its prolific adoption, with over 1130 studies published in the last five years. The model's high genetic homology, optical transparency, and rapid development offer an ethically favorable system for the high-throughput assessment of nanotoxicity, biodistribution, and therapeutic efficacy. This review positions the zebrafish as an indispensable intermediate filter to prioritize lead candidates and deconvolute mechanistic pathways for nanomaterials. Critically, the model is best suited for preliminary in vivo evaluation; its findings necessitate subsequent validation in established mammalian models prior to any human translation. Systematically reviewing the literature, we organize nanomaterials by chemical composition and map their respective applications to different disease areas, analyzing the type of nanomaterial and its properties and therapeutic effectiveness. We detail how its integration with automated imaging, microinjection, and artificial intelligence (AI) is powering sophisticated high content screening pipelines, drastically reducing preclinical costs and timelines and with the possibility of developing personalized medicine. By improving predictive validity and serving as a bridge between in vitro trials and preclinical studies in higher-order animals, the zebrafish model streamlines the translation pathway, accelerating the development of therapies within the nanoworld.