Communications Chemistry, Published online: 27 August 2026; doi:10.1038/s42004-026-02170-9Protein–nucleic acid interactions are pivotal in regulating cellular processes, yet identifying weakly bound proteins remains challenging. Here, the authors introduce a photocatalyst-modified DNA G-quadruplex approach for precise profiling of G4-interacting proteins, revealing insights into their roles in biological processes and advancing our understanding of nucleic acid regulation.