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The inflammatory microenvironment surrounding cancer cells accelerates the reproduction of pathogenic\u00a0bacteria, and the polyketide synthase\u2010catalyzed metabolites generated by these bacteria correspondingly promote cancer cell proliferation, thus forming a detrimental cancer\u2010bacteria cycle. Here, we demonstrated that gasdermin\u2010D (GSDMD) (the executive protein of cell pyroptosis) improves gut dysbiosis in an obese mouse model, whereas GSDMD deficiency promotes CRC development in these mice, thus suggesting that GSDMD is a potential target for CRC therapy. In this study, we designed a novel dual\u2010targeted GSH\u2010sensitive nanodrug delivery system aimed at specifically delivering mRNA encoding the N\u2010terminal domain of GSDMD (GSDMD\u2010N mRNA) to local CRC tissues. Such a system helps to induce pyroptosis in CRC cells and corrects gut dysbiosis caused by the tumor microenvironment, thus achieving a dual regulatory effect. This study contributes to the current understanding of the pathophysiological functions of GSDMD\u2010mediated pyroptosis in CRC and suggests a new strategy for precise CRC therapy targeting GSDMD, thereby providing a solid theoretical basis and experimental evidence for the development of mRNA nanodrug delivery systems.<\/jats:p>","DOI":"10.1002\/smll.74889","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T10:03:22Z","timestamp":1785492202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oral GSDMD\u2010N mRNA Nanoparticle\u2010Induced Pyroptosis for the Treatment of Colorectal Cancer"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-9705","authenticated-orcid":false,"given":"Mingming","family":"Song","sequence":"first","affiliation":[{"name":"School of Pharmacy Anhui Medical University  Hefei 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