A Biomimetic Dual‐Targeting Nano‐APA‐Editor Reprograms the 3'UTR Landscape for Tongue Squamous Cell Carcinoma Therapy

ABSTRACT Targeting post‐transcriptional dysregulation of tumor suppressors represents a new frontier in cancer therapy. 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‐repressed, long‐3'UTR isoforms. To therapeutically “re‐engineer” this APA switch, we design a “Nano‐APA‐editor.” This platform features an HMSN core with an sgRNA‐NUDT21 payload and a hierarchical targeting strategy: a cancer‐educated dendritic cell (DC) membrane for biomimetic camouflage and homotypic affinity, “gated” by a TA‐aptamer for final precision. This system enables potent and selective NUDT21 silencing, driving a shift toward short‐3'UTR isoforms. Consequently, the Nano‐APA‐editor 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‐down) and functional restoration (PTEN‐, WEE1‐, TGF‐β‐up). This work validates a “post‐transcriptional re‐engineering” strategy, executed by a logically designed nanoplatform, as a powerful and safe modality for precision gene therapy.