Scalable integration and prediction of unpaired single-cell and spatial multi-omics via regularized disentanglement

Deciphering cellular states requires methods capable of integrating large-scale heterogeneous single-cell and spatial omics data. However, these data are typically unpaired due to destructive assays and further confounded by modality heterogeneity, technical noise, and immense scale. Here we present scMRDR, a scalable computational framework based on regularized disentangled representation learning for integrating fully unpaired single-cell and spatial multi-omics datasets. Built on a unified and structure-preserving architecture, scMRDR removes the need for pairing supervision while maintaining computational efficiency, enabling scaling to large datasets spanning multiple disparate omics modalities. Across diverse real-world benchmarks, scMRDR demonstrates strong performance in batch correction, modality alignment, and biological signal preservation. The framework further supports cross-modal translation across omics modalities and enables spatial coordinate imputation for non-spatial single-cell datasets using a reference atlas. The resulting spatial mapping allows spatially resolved analyses, including identification of spatially variable genes and characterization of epigenetic regulatory programs in their native tissue context. These capabilities position scMRDR as a scalable and versatile framework for large-scale multi-omics integration.