This resource article introduces Perturb-Multimodal (Perturb-Multi), an innovative platform integrating imaging and sequencing for pooled genetic screening in intact mammalian tissues. The method captures in situ genotypes and multiple RNA-protein phenotypes through RCA-MERFISH, and enables in vivo CRISPR screening while preserving complete transcriptomes through fixed-cell Perturb-seq. The article elaborates on these technical innovations, using mouse liver as an example to demonstrate applications in exploring genetic regulation of liver function, cellular zonation, stress responses, and steatosis. Using this platform, researchers generated multimodal transcriptional and morphological tissue atlases of the liver and identified key gene regulators influencing cellular states under different physiological conditions, revealing new insights into genotype-phenotype relationships.
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