The study focuses on developing self-deliverable CRISPR ribonucleoproteins (RNPs) for genome editing in the brain. CRISPR-Cas technology, adapted from bacterial immune systems, has revolutionized genome engineering, but its delivery to the central nervous system (CNS) remains challenging due to low efficiency and cell toxicity. The researchers engineered self-deliverable RNPs by fusing cell-penetrating peptides (CPPs) to the C-terminus of Cas9, enhancing cellular uptake and genome editing efficiency. They identified a potent construct with three copies of A22p, a peptide derived from human semaphorin-3a, which showed significantly improved editing efficacy compared to other constructs. In vitro and in vivo tests demonstrated that these self-deliverable Cas9 RNPs could effectively edit clinically relevant genes in neural progenitor cells and neurons, respectively. The study highlights the potential of self-deliverable RNPs for safe and efficient genome editing in the brain, offering a promising platform for treating genetic disorders in the CNS.The study focuses on developing self-deliverable CRISPR ribonucleoproteins (RNPs) for genome editing in the brain. CRISPR-Cas technology, adapted from bacterial immune systems, has revolutionized genome engineering, but its delivery to the central nervous system (CNS) remains challenging due to low efficiency and cell toxicity. The researchers engineered self-deliverable RNPs by fusing cell-penetrating peptides (CPPs) to the C-terminus of Cas9, enhancing cellular uptake and genome editing efficiency. They identified a potent construct with three copies of A22p, a peptide derived from human semaphorin-3a, which showed significantly improved editing efficacy compared to other constructs. In vitro and in vivo tests demonstrated that these self-deliverable Cas9 RNPs could effectively edit clinically relevant genes in neural progenitor cells and neurons, respectively. The study highlights the potential of self-deliverable RNPs for safe and efficient genome editing in the brain, offering a promising platform for treating genetic disorders in the CNS.