Expansion omics: from expansion microscopy to spatial omics

Abstract Tissue expansion, originally developed for super-resolution imaging, has become a foundation for expansion omics (ExO), a growing field that uses physical tissue expansion to enable spatially resolved omics profiling. In this perspective, we explore how ExO integrates multi-omics through chemical anchoring strategies that ensure selective retention of diverse molecular species, together with improved spatial resolution from the subcellular resolution for profiling to the sub-nanometer scale for imaging, allowing precise detection of biomolecules and their link with biological function. These capabilities have empowered tissue expansion to be successfully applied across multiple spatial omics modalities, including epigenomics, transcriptomics, proteomics, and lipidomics, enabling high-resolution mapping of chromatin states, gene expression, protein localization, and lipid distributions. Moreover, ExO supports spatial multi-omics approaches that jointly capture and correlate multiple biomolecular dimensions within the same tissue context. However, challenges remain in expansion resolution, molecular retention, hydrogel adaptability, data scalability, and AI-driven analysis. As tissue expansion evolves, its integration of super-resolution imaging and spatial omics establishes it as a core technology for whole-slide, single-cell multi-omics and the development of the Artificial Intelligence Virtual Cell, advancing spatial biology and medicine.