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However, measurement quality depends on RNA integrity, and the modern tissue preservation toolbox was not designed to protect this highly labile molecule. Here we leverage MERFISH to show that tissue-dependent differences in endogenous RNase activity can shape spatial transcriptomics data quality for different preservation methods and that RNase-activity-guided protocol optimization can improve data quality. In parallel, we introduce an RNA-aware pan-tissue preservation approach, Rapid Inhibition and Permanent Inactivation of Nucleases (RIPIN), that rapidly stabilizes samples with a broad-spectrum RNase inhibitor while permitting slow, chemical inactivation. RIPIN produces high-quality MERFISH measurements in all profiled human and mouse tissues, is compatible with clinical workflows, and is easily integrated with frozen or paraffin sectioning. By highlighting how RNA integrity can be lost during tissue processing, our work may inspire the next generation of RNA-aware histology methods.<\/jats:p>","DOI":"10.64898\/2026.09.07.749899","type":"posted-content","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:45:15Z","timestamp":1789188315000},"source":"Crossref","is-referenced-by-count":1,"title":["RNA-aware tissue preservation workflows for high-quality spatial transcriptomics"],"prefix":"10.64898","author":[{"given":"Paolo","family":"Cadinu","sequence":"first","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian A.","family":"Reardon-Lochbaum","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA"},{"name":"Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA"},{"name":"Division of Pediatric Hematology-Oncology, Boston Children\u2019s Hospital\/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"Kalemaki","sequence":"additional","affiliation":[{"name":"Divisions of Stroke, Cerebrovascular, and Critical Care Neurology, Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, 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Medical School, Boston, MA, USA"},{"name":"Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham & Women\u2019s Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan B.","family":"Cantor","sequence":"additional","affiliation":[{"name":"Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA"},{"name":"Division of Pediatric Hematology-Oncology, Boston Children\u2019s Hospital\/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3836-3101","authenticated-orcid":false,"given":"Jeffrey R.","family":"Moffitt","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA"},{"name":"Broad 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