Short cell-penetration peptide conjugated bioreducible polymer enhances gene editing of CRISPR system

CRISPR-based gene therapy offers precise targeting and specific editing of disease-related gene sequences, potentially yielding long-lasting treatment effects. However, efficient delivery remains a significant challenge for its widespread application. In this study, we design a novel short peptide-conjugated bioreducible polymer named TSP^scp as a safe and effective delivery vector for the CRISPR system. Our results show that TSP^scp markedly boosts transcriptional activation and genome editing activities of multiple CRISPR systems as confirmed by decomposition-seq and Deep-seq, which is resulted from its capability in facilitating delivery of plasmid DNA by promoting cellular uptake and lysosomal escape. Additionally, TSP^scp further enhances genome editing of CRISPR by delivery of minicircle DNA, a condensed form of regular plasmid DNA. More importantly, TSP^scp significantly improves delivery and genome editing of CRISPR system in vivo. In summary, our study highlights TSP^scp as a promising delivery tool for CRISPR applications in vivo.