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Here, we identify the alternative polyadenylation (APA) regulator NUDT21 as a pivotal therapeutic target in oral squamous cell carcinoma (OSCC). NUDT21 is highly upregulated, correlating strongly with poor survival and advanced clinical stage. We outline a pathogenic mechanism whereby NUDT21 drives this phenotype by forcing a network of tumor suppressor transcripts, notably PTEN, into translationally\u2010repressed, long\u20103'UTR isoforms. To therapeutically \u201cre\u2010engineer\u201d this APA switch, we design a \u201cNano\u2010APA\u2010editor.\u201d This platform features an HMSN core with an sgRNA\u2010NUDT21 payload and a hierarchical targeting strategy: a cancer\u2010educated dendritic cell (DC) membrane for biomimetic camouflage and homotypic affinity, \u201cgated\u201d by a TA\u2010aptamer for final precision. This system enables potent and selective NUDT21 silencing, driving a shift toward short\u20103'UTR isoforms. Consequently, the Nano\u2010APA\u2010editor effectively reinstates PTEN and associated suppressors and inhibits multiple malignant phenotypes in vitro. In an orthotopic OSCC model, it demonstrates profound tumor regression, outperforming conventional chemotherapy (PTX) with excellent biocompatibility. In vivo analysis confirmed target engagement (NUDT21\u2010down) and functional restoration (PTEN\u2010, WEE1\u2010, TGF\u2010\u03b2\u2010up). This work validates a \u201cpost\u2010transcriptional re\u2010engineering\u201d strategy, executed by a logically designed nanoplatform, as a powerful and safe modality for precision gene therapy.<\/jats:p>","DOI":"10.1002\/advs.76126","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T11:48:24Z","timestamp":1781524104000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Biomimetic Dual\u2010Targeting Nano\u2010APA\u2010Editor Reprograms the 3'UTR Landscape for Tongue Squamous Cell Carcinoma Therapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Yiran","family":"Ao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Hubei Key Laboratory of Stomatology Key Laboratory of Oral Biomedicine Ministry of Education School &amp; Hospital of Stomatology Wuhan University  Wuhan P. R. 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