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While 3D cell cultures are more physiologically relevant models \u2013 especially for studying drug perturbations \u2013 they remain challenging to image because light scatters before it reaches the cultures\u2019 interior. Here, we introduce a scalable method to adapt Cell Painting for 3D spheroids. We show that tissue-clearing, a technique that makes spheroids transparent, combined with a focusing routine that locates spheroids on the fly, enables Cell Painting at single-cell level inside intact spheroids. By profiling 52 clinically relevant drugs, we show that single-cell fingerprints clustered by biological pathway and resolved drug effects more robustly than those of flattened spheroid-wide views. Notably, the effect of two drugs, 5-fluorouracil and olaparib, nearly indistinguishable in 2D monolayers, diverged in spheroids. This finding was then corroborated by DNA-damage, cell-cycle, and gene-expression assays. The workflow runs on a spinning-disk confocal microscope in a standard 384-well plate format, making single-cell 3D profiling accessible to laboratories already performing Cell Painting.<\/jats:p>","DOI":"10.1038\/s41467-026-78596-5","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T09:02:43Z","timestamp":1792573363000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-content morphological profiling by Cell Painting in 3D spheroids"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0807-8481","authenticated-orcid":false,"given":"Christa","family":"Ringers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Holmberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Larsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bomi","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1565-6155","authenticated-orcid":false,"given":"Malin","family":"Jarvius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Luchniak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Ros\u00e9n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Johansson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina","family":"Georgiev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8658-5967","authenticated-orcid":false,"given":"Brinton","family":"Seashore-Ludlow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1047-988X","authenticated-orcid":false,"given":"Torkild","family":"Visnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3357-425X","authenticated-orcid":false,"given":"\u00c5smund","family":"Flobak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Carreras-Puigvert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8083-2864","authenticated-orcid":false,"given":"Ola","family":"Spjuth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"key":"78596_CR1","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nrd3480","volume":"10","author":"DC Swinney","year":"2011","unstructured":"Swinney, D. 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