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Through integrated bioinformatics analysis of in\u2010house and public datasets, we systematically identified miR\u201021 as the most significantly upregulated oncomiR in PDAC, showing strong correlation with poor patient prognosis. RNA\u2010targeted degradation has emerged as a promising strategy for cancer treatment, enabling precise disruption of oncogenic signaling by degrading disease\u2010driving non\u2010coding RNAs. Nevertheless, poor tissue penetration and insufficient tumor specificity limit its therapeutic potential in pancreatic cancer, owing to the dense fibrotic stroma and heterogeneous target expression. Herein, we developed a dual\u2010targeting, bioresponsive Nb\u2010RIBOTAC (Nb\u2010Fc\u2010Val\u2010Cit\u2010RIBOTAC), engineered by conjugating a cathepsin B\u2013responsive linker to bridge an EGFR\u2010targeting nanobody (Nb\u2010Fc fusion) with a miR\u201021\u2013specific RIBOTAC module. This rationally designed therapeutic achieved potent and selective miR\u201021 degradation in orthotopic PDAC models, with 60% target knockdown while completely sparing normal tissues, leading to significant tumor growth inhibition. Our study establishes a transformative paradigm bridging bioinformatic identification with precision RNA degradation technology, offering new therapeutic possibilities for PDAC treatment. The target selection strategy and modular design principles described herein may be broadly applicable to other challenging malignancies.<\/jats:p>","DOI":"10.1002\/advs.76575","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T10:12:16Z","timestamp":1784196736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell\u2010Selective Delivery of RIBOTACs via an Anti\u2010EGFR Nanobody for Pancreatic Cancer Treatment"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7816-2851","authenticated-orcid":false,"given":"Tianli","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Surgery The Chinese University of Hong Kong  Shatin Hong Kong SAR China"},{"name":"Department of Pathology School of Clinical Medicine Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong Hong Kong SAR 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