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Compared to traditional antibodies, aptamers, which are single\u2010stranded oligonucleotides with high affinity and low immunogenicity, offer an ideal platform for discovering novel biomarkers. Based on this approach, we used the Cell\u2010SELEX strategy to develop a high\u2010affinity aptamer\u2010based probe, WHY\u20103E, which successfully identified the cellular prion protein (PrPC) as a key molecular target. We observed that PrPC was significantly upregulated in CRC tissues, strongly correlating with unfavorable clinical outcomes. Functionally, PrPC promotes malignant phenotypes, including migration and invasion, by regulating MSN. Mechanistically, we revealed that PrPC physically translocates from the cell surface to the cytoplasm via endocytosis. Once internalized, it interacts with the STAT3\u2010NTD and LYN\u2010SH domains, facilitating the ternary complex formation that enhances LYN\u2010mediated STAT3 phosphorylation, ultimately increasing MSN transcriptional activity. Moreover, the deubiquitinase USP18 stabilizes PrPC by removing its Lys48\u2010linked ubiquitin chains, ensuring the continuous activation of this oncogenic axis. Notably, the WHY\u20103E aptamer achieved 90.6% sensitivity and 89.0% specificity in detecting PrPC\u2010positive circulating exosomes in patient cohorts. These findings deepen the mechanistic understanding of CRC progression and offer novel strategic avenues for PrPC\u2010targeted aptamer applications in non\u2010invasive diagnostics.<\/jats:p>","DOI":"10.1002\/advs.75758","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T15:15:51Z","timestamp":1779203751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aptamer\u2010Targeted PrPC Drives Colorectal Cancer Metastasis via a LYN\u2010STAT3 Complex and Enables Liquid Biopsy Detection"],"prefix":"10.1002","volume":"13","author":[{"given":"Chunlin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Colorectal Cancer Surgery The Second Affiliated Hospital of Harbin Medical University  Harbin Heilongjiang P. R. 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