Stereo-cell: spatial enhanced resolution single-cell sequencing with high-density DNA nanoball-patterned arrays

The advent of state-of-the-art single-cell sequencing technology has dramatically advanced our ability to profile individual cells in depth, providing an unprecedented view of the complexity of biological systems at the single-cell level. However, existing high-throughput single-cell techniques have encountered limitations, including a narrow range of cell throughput, constraints on cell size, and a lack of simplicity and flexibility. Here, we introduce Stereo-cell, a cutting-edge approach for cell transcriptome profiling that conducts spatial enhanced resolution single-cell sequencing using high-density DNA nanoball (DNB)-patterned arrays. This method has seamlessly integrated instrument-independent cell capturing, cell imaging, and whole-cell transcriptome profiling, yielding high-fidelity cell profiles with competitive detection sensitivity, enhanced scalable cell throughput, and superior unbiased cell capture capabilities. Moreover, Stereo-cell has exhibited strong technical extensibility: it has effectively integrated with multiplex immunofluorescence (mIF) assays, enabled in situ detection of cell-cell interactions and the microenvironment of cultured cells, accommodated large-sized cells and microstructures, and shown the potential for subcellular RNA localization detection. Thus, Stereo-cell presents a highly compatible, versatile, and scalable solution, revolutionizing single-cell transcriptomics (scRNA-seq) by transitioning from conventional approaches to an innovative digital cellular chip technique.