This article describes the development of self-deliverable CRISPR ribonucleoproteins (RNPs) for efficient genome editing in the brain. CRISPR-Cas technology, derived from bacterial immune systems, enables precise genome editing by using an RNA guide to direct the Cas protein to specific DNA sequences. While CRISPR-Cas has shown promise in treating genetic disorders, delivering the editing components to the brain remains a challenge due to the limitations of viral delivery methods, such as immunogenicity and insertional mutagenesis. The study introduces self-deliverable RNPs that can efficiently enter cells without the need for additional helper molecules. By fusing CRISPR-Cas9 with cell-penetrating peptides (CPPs), the researchers created RNPs that can deliver genome editing tools directly into neural progenitor cells and neurons. The most effective CPPs identified were derived from human semaphorin-3a (A22p) and Bac7, which significantly improved genome editing efficiency. The self-deliverable Cas9 RNPs were tested in mice, showing robust genome editing in the striatum when injected directly. The study also demonstrated that these RNPs can effectively edit genes associated with neurological disorders, such as tyrosine hydroxylase (TH) and metabotropic glutamate receptor 5 (mGluR5), in the mouse brain. The results indicate that self-deliverable RNPs offer a safe and efficient method for genome editing in the brain, with minimal cytotoxicity compared to traditional delivery methods. The study highlights the potential of self-deliverable CRISPR RNPs as a promising tool for treating genetic disorders in the central nervous system. The findings suggest that further engineering of these RNPs could lead to broader applications in therapeutic genome editing.This article describes the development of self-deliverable CRISPR ribonucleoproteins (RNPs) for efficient genome editing in the brain. CRISPR-Cas technology, derived from bacterial immune systems, enables precise genome editing by using an RNA guide to direct the Cas protein to specific DNA sequences. While CRISPR-Cas has shown promise in treating genetic disorders, delivering the editing components to the brain remains a challenge due to the limitations of viral delivery methods, such as immunogenicity and insertional mutagenesis. The study introduces self-deliverable RNPs that can efficiently enter cells without the need for additional helper molecules. By fusing CRISPR-Cas9 with cell-penetrating peptides (CPPs), the researchers created RNPs that can deliver genome editing tools directly into neural progenitor cells and neurons. The most effective CPPs identified were derived from human semaphorin-3a (A22p) and Bac7, which significantly improved genome editing efficiency. The self-deliverable Cas9 RNPs were tested in mice, showing robust genome editing in the striatum when injected directly. The study also demonstrated that these RNPs can effectively edit genes associated with neurological disorders, such as tyrosine hydroxylase (TH) and metabotropic glutamate receptor 5 (mGluR5), in the mouse brain. The results indicate that self-deliverable RNPs offer a safe and efficient method for genome editing in the brain, with minimal cytotoxicity compared to traditional delivery methods. The study highlights the potential of self-deliverable CRISPR RNPs as a promising tool for treating genetic disorders in the central nervous system. The findings suggest that further engineering of these RNPs could lead to broader applications in therapeutic genome editing.