Mohamedshah et al. present an enzymatic strategy for covalently linking nuclear localization sequence (NLS) peptides to DNA cassettes by incorporating a strained cyclooctyne and using SPAAC chemistry, greatly enhancing transfection efficiency compared to previous methods. [ https://www.nature.com/articles/s41467-025-68167-5](https://www.nature.com/articles/s41467-025-68167-5)

Efficient nuclear delivery of DNA remains a major challenge in non-viral gene therapy. Here the authors present an improved workflow for generating DNA oligonucleotide-peptide conjugates which are ligated to linear DNA and achieve nuclear localization.