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Here, we present Ex\u2010spRandom, a highly sensitive platform that overcomes this limitation by directly converting diverse, fragmented RNA biotypes into stably anchored cDNA through the integration of random\u2010primed in situ cDNA synthesis chemistry with interpenetrating polymer network (IPN)\u2010based tissue expansion chemistry. This physicochemical synergy physically decrowds the dense FFPE matrix, directly converting highly fragmented host and microbial RNAs into stably anchored cDNA. Consequently, Ex\u2010spRandom improves spatial signal confinement while enabling the detection of nearly 10,000 median genes per 50\u2010\u00b5m spatial bin. Leveraging this synergistic high resolution and sensitivity, the platform captures over 44,000 unique host genes, enabling the precise delineation of continuous neurodevelopmental trajectories in the complex embryonic eye. Furthermore, Ex\u2010spRandom achieves simultaneous, spatial profiling of host epithelial architecture and microbial transcript signals in the colon, detecting over 150,000 unique microbial genes. Ultimately, this scalable platform establishes a framework for sensitive, cross\u2010kingdom spatial profiling in archival FFPE tissues.<\/jats:p>","DOI":"10.1002\/advs.77219","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T11:44:16Z","timestamp":1786967056000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Highly Sensitive Spatial Host\u2010Microbiome Transcriptomics in FFPE Tissues via Iterative Hydrogel Expansion"],"prefix":"10.1002","author":[{"given":"Shunji","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine of The First Affiliated Hospital &amp; Liangzhu Laboratory Zhejiang University School of Medicine Zhejiang University  Hangzhou China"},{"name":"College of Biomedical Engineering and Instrument Science Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6338-3053","authenticated-orcid":false,"given":"Mengyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine of The First Affiliated Hospital &amp; Liangzhu Laboratory Zhejiang University School of Medicine Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaye","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine of The First Affiliated Hospital &amp; Liangzhu Laboratory Zhejiang University School of Medicine Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyi","family":"Zhu","sequence":"additional","affiliation":[{"name":"M20 Genomics  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhu","sequence":"additional","affiliation":[{"name":"M20 Genomics  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6229-2112","authenticated-orcid":false,"given":"Ziye","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine of The First Affiliated Hospital &amp; Liangzhu Laboratory Zhejiang University School of Medicine Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2456-2115","authenticated-orcid":false,"given":"Yuan","family":"Liao","sequence":"additional","affiliation":[{"name":"M20 Genomics  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2820-4243","authenticated-orcid":false,"given":"Yongcheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine of The First Affiliated Hospital &amp; Liangzhu Laboratory Zhejiang University School of Medicine Zhejiang University  Hangzhou China"},{"name":"College of Biomedical Engineering and Instrument Science Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010022\u201001409\u20102"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010020\u201001033\u2010y"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576\u2010021\u201000370\u20108"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/448959a"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4279"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010024\u201002325\u20103"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201051577\u20102"},{"key":"e_1_2_14_9_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.aaf2403","article-title":"Visualization And Analysis Of Gene Expression In Tissue Sections By Spatial Transcriptomics","volume":"353","author":"St\u00e5hl P. 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