Designer Cellular Spheroids with DNA Origami for Drug Screening

Abstract In vitro models are crucial for drug screening, yet they often fail to accurately reflect human physiological responses. While 3D cell cultures aim to simulate human tissues, many lack the detailed complexity and interaction of various cell types found in actual tissues. Additionally, integrating these models with high-throughput drug screening remains a challenge. Current models can't strike the balance between capturing the complexity of human diseases and being suitable for large-scale drug tests. Here we introduce a method that uses self-assembling Nucleic-Acid-nanostructures-decorated-living-Cells, termed NACs, to create spheroids with a customizable 3D layout. To demonstrate its uniqueness, our method effectively creates designer 3D liver spheroids by combining hepatocytes with different non-parenchymal cells, leading to improved drug sensitivity and detailed modeling of complex chronic diseases and immune-stromal interactions. Our approach achieves a high level of biological detail while being standardized and straightforward to construct with the potential for large-scale drug discovery applications. By combining the precision of DNA nanotechnology with advanced cell culture techniques, we're streamlining human-centric models, balancing complexity with standardization, to boost drug screening efficiency.