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For nearly 70 years, uranyl salts like uranyl acetate (UA) have been the gold\u2010standard ns\/psTEM\u2010stains. However, mounting safety concerns due to their high toxicity and radioactivity have led to stricter regulations and expensive licensing requirements. Consequently, there is an urgent global demand for safer, more sustainable stains that deliver uranyl\u2010comparable, high\u2010quality ns\/psTEM. Here, the commercially available stain\u2010alternatives UranyLess, UAR, UA\u2010Zero, PTA, STAIN 77, Nano\u2010W, NanoVan, and lead citrate are systematically assessed against UA. The stains are evaluated regarding their contrast, resolution, stain\u2010distribution, and ease\u2010of\u2010use in ns\/psTEM across a diverse sample set, including polymethylmethacrylate\u2010nanoplastics, phosphatidylcholine\u2010liposomes, Influenza\u2010A viruses, globular ferritin, fibrillar pyruvate kinase amyloids, and human lung\u2010carcinoma cell\u2010sections. It is shown that for this variety of samples, a ready\u2010to\u2010use uranyl\u2010alternative is commercially available with comparable or even superior ns\/psTEM\u2010performance to UA using an efficient staining\u2010protocol. Furthermore, the <jats:italic>GUIDE4U<\/jats:italic> tool is developed for the fast identification of the appropriate uranyl\u2010replacements for each sample of interest, saving ns\/psTEM\u2010users time and costs while ensuring excellent staining results for ultrastructural analysis, thereby further catalyzing the use of safer stains.<\/jats:p>","DOI":"10.1002\/adhm.202404870","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T02:44:46Z","timestamp":1745981086000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Systematic Comparison of Commercial Uranyl\u2010Alternative Stains for Negative\u2010 and Positive\u2010Staining Transmission Electron Microscopy of Organic Specimens"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4524-9905","authenticated-orcid":false,"given":"Vera M.","family":"Kissling","sequence":"first","affiliation":[{"name":"Nanomaterials in Health Laboratory Department of Materials Meet Life Swiss Federal Laboratories for Materials Science and Technology (Empa)  St. Gallen 9014 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0481-4882","authenticated-orcid":false,"given":"Stephanie","family":"Eitner","sequence":"additional","affiliation":[{"name":"Nanomaterials in Health Laboratory Department of Materials Meet Life Swiss Federal Laboratories for Materials Science and Technology (Empa)  St. Gallen 9014 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6133-5088","authenticated-orcid":false,"given":"Davide","family":"Bottone","sequence":"additional","affiliation":[{"name":"Nanomaterials in Health Laboratory Department of Materials Meet Life Swiss Federal Laboratories for Materials Science and Technology (Empa)  St. Gallen 9014 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7732-9435","authenticated-orcid":false,"given":"Gea","family":"Cereghetti","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases Department of Chemistry University of Cambridge  Cambridge CB2 1EW UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0079-4344","authenticated-orcid":false,"given":"Peter","family":"Wick","sequence":"additional","affiliation":[{"name":"Nanomaterials in Health Laboratory Department of Materials Meet Life Swiss Federal Laboratories for Materials Science and Technology (Empa)  St. Gallen 9014 Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.4.4.475"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(59)90237-9"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/01478885.2024.2306076"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics11061063"},{"key":"e_1_2_10_5_1","unstructured":"D. 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