Black Phosphorus Quantum Dots Cause Nephrotoxicity in Organoids, Mice, and Human Cells

Quantum dots (QDs) have numerous potential applications in lighting, engineering, and biomedicine. QDs are mainly excreted through the kidney due to their ultrasmall sizes; thus, the kidneys are target organs of QD toxicity. Here, an organoid screening platform is established and used to study the nephrotoxicity of QDs. Organoids are templated from monodisperse microfluidic Matrigel droplets and found to be homogeneous in both tissue structure and functional recapitulation within a population and suitable for the quantitative screening of toxic doses. Kidney organoids are proved displaying higher sensitivity than 2D‐cultured cell lines. Similar to metal‐containing QDs, black phosphorus (BP)‐QDs are found to have moderate toxicity in the kidney organoids. The nephrotoxicity of BP‐QDs are validated in both mice and human renal tubular epithelial cells. BP‐QDs are also found to cause insulin insensitivity and endoplasmic reticulum (ER) stress in the kidney. Furthermore, ER stress‐related IRE1α signaling is shown to mediate renal toxicity and insulin insensitivity caused by BP‐QDs. In summary, this work demonstrates the use of constructed kidney organoids as 3D high‐throughput screening tools to assess nanosafety and further illuminates the effects and molecular mechanisms of BP‐QD nephrotoxicity. The findings will hopefully enable improvement of the safety of BP‐QD applications. This study establishes a high‐throughput screening platform based on organoids that is used to evaluate the nephrotoxicity of quantum dots (QDs). Black phosphorus (BP)‐QDs have toxic effects on the kidney, as shown by screening on the organoids. The nephrotoxicity of BP‐QDs is validated in mice and human renal tubular epithelial cells. Endoplasmic reticulum stress IRE1α signaling is proven to mediate renal toxicity and insulin insensitivity caused by BP‐QDs.