<i>In vivo</i> multiomic Perturb-seq with enhanced nuclear gRNA capture

<i>In vivo</i> CRISPR screening with joint transcriptomic and chromatin readouts has been limited by inefficient recovery of gRNAs from nuclei. Here, we developed <i>in vivo</i> multiomic Perturb-seq, an effective platform combining nuclear transcript anchoring with gRNA-specific capture and amplification to enable high-fidelity, high-recovery gRNA assignment and scalable perturbation-resolved single-nucleus multiomics. Applying this platform to interrogate neurodevelopmental disorder risk genes in the developing cortex reveals cell-type-specific transcriptomic and epigenomic perturbation phenotypes.