The circadian clock coordinates the daily rhythmicity of biological processes, and its dysregulation is associated with various human diseases. Despite the direct targeting of rhythmic genes by many prevalent and World Health Organization (WHO) essential drugs, traditional approaches can't satisfy the need of explore multi‐timepoint drug administration strategies across a wide range of drugs. Here, droplet‐engineered primary liver organoids (DPLOs) are generated with rhythmic characteristics in 4 days, and developed Chronotoxici‐plate as an in vitro high‐throughput automated rhythmic tool for chronotherapy assessment within 7 days. Cryptochrome 1 (Cry1) is identified as a rhythmic marker in DPLOs, providing insights for rapid assessment of organoid rhythmicity. Using oxaliplatin as a representative drug, time‐dependent variations are demonstrated in toxicity on the Chronotoxici‐plate, highlighting the importance of considering time‐dependent effects. Additionally, the role of chronobiology is underscored in primary organoid modeling. This study may provide tools for both precision chronotherapy and chronotoxicity in drug development by optimizing administration timing.

中文翻译：

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用于药物毒性评估的含有液滴工程节律性肝脏类器官的 Chronotoxixi-Plate

生物钟协调生物过程的日常节律，其失调与多种人类疾病有关。尽管许多流行的药物和世界卫生组织（WHO）的基本药物直接靶向节律基因，但传统方法无法满足探索多种药物的多时间点给药策略的需要。在这里，液滴工程原代肝类器官 (DPLO) 在 4 天内生成了具有节律特征的药物，并开发了 Chronotoxin-plate 作为体外高通量自动化节律工具，用于在 7 天内评估时间疗法。隐花色素 1 (哭泣1）被确定为 DPLO 中的节律标记，为快速评估类器官节律性提供见解。使用奥沙利铂作为代表性药物，Chronotoxixi 板上的毒性显示出时间依赖性变化，强调了考虑时间依赖性效应的重要性。此外，时间生物学在初级类器官建模中的作用也得到了强调。这项研究可以通过优化给药时机，为药物开发中的精确时间疗法和时间毒性提供工具。