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Although numerous photo-crosslinking approaches have been successfully employed, they often suffer from common limitations, including low reaction yields, the need for long exposure times, and irradiation-induced cellular damage from heat, desiccation, or side reactions. We recently showed that 365 nm light-emitting diodes enable rapid, biorthogonal protein\u2013DNA crosslinking in living cells, incurring minimal photodamage. Here, we generalize this approach and demonstrate that high-intensity, longwave UV light reduces the irradiation time for in-cell photo-crosslinking reactions by up to 1000-fold, allowing protein\u2013drug, protein\u2013protein, protein\u2013DNA, and protein\u2013RNA interactions to be fixed within seconds. Benchmarking this rapid photo-activation for the analysis of RNA-interacting proteomes responding to RNA-binding drugs or UV-induced RNA damage, we demonstrate both qualitative and quantitative advantages of controlled, high-intensity UV irradiation, uncovering emergent experimental opportunities that were previously inaccessible to light-activated chemistry in intact cells and tissues.<\/jats:p>","DOI":"10.1093\/nar\/gkag339","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T11:29:09Z","timestamp":1776166149000},"source":"Crossref","is-referenced-by-count":2,"title":["Rapid photo-crosslinking in living cells reveals protein\u2013nucleic acid dynamics on a timescale of minutes"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2540-2535","authenticated-orcid":false,"given":"Jakob","family":"Trendel","sequence":"first","affiliation":[{"name":"Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, 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